Chronic Inflammation in The Pathogenesis of Benign Prostatic Hyperplasia

Chronic inflammation in the pathogenesis
of benign prostatic hyperplasia

1. B. Fibbi1,
2. G. Penna2,
3. A. Morelli1,
4. L. Adorini2,
5. M. Maggi1
Article first published online: 8 JUN 2009
DOI: 10.1111/j.1365-2605.2009.00972.
Summary
Benign prostatic hyperplasia (BPH) is a common disorder affecting 5080% of the aged male
population. Androgens and age have been traditionally considered the main determinants of
prostate enlargement, but in the last years a potentially important role of chronic
inflammation in BPH pathogenesis has emerged. Bacterial and non-infectious chronic
prostatitis could represent inciting factors leading to tissue hyperproliferation, possibly via
the recently demonstrated antigen-presenting capacity of prostatic stromal cells, enabling
them to induce and sustain intraglandular immune responses. The prostate growth-promoting
chemokine IL-8 could represent a direct link between chronic prostate inflammation and
autocrine/paracrine stromal cell proliferation, in agreement with its marked secretion induced
in BPH stromal cells by a combination of Th1 and Th17 cell-derived inflammatory cytokines.
BPH stromal cells express the vitamin D receptor (VDR), which is up-regulated by exposure
to inflammatory stimuli. The non-hypercalcaemic VDR agonist elocalcitol, shown to arrest
BPH development by decreasing the intra-prostatic androgen signalling without directly
interfering with systemic androgen action, exerts immunoregulatory and anti-inflammatory
properties in different prostatic pathology characterized by growth and inflammation. The
mechanism of action of VDR agonists supports an important role of chronic inflammation in
BPH pathogenesis and strengthens the concept of these agents as a therapeutic option for
pharmacological treatment of BPH.
Introduction
Benign prostatic hyperplasia (BPH) is the most frequent benign neoplasm in ageing men and
one of the most common chronic conditions in the male population, with a histological
prevalence at autopsy of 50% in men aged 5060 years and of 90% over 80 years [McVary
(2006)]. As most chronic diseases, BPH is progressive: it requires a long period to evolve
from earlier tissue alterations to clinical onset with lower urinary tract symptoms (LUTS)
[Jacobsen et al. (1996); Roberts et al. (2000); Fitzpatrick (2006)], and, if untreated, it often
complicates with bladder dysfunction and hypertrophy possibly leading to acute urinary
retention (AUR) [McNeal (1990); Jacobsen et al. (1997); Kolman et al. (1999); McConnell
et al. (2003); Roehrborn (2006); Roehrborn et al. (2008)].
Histologically, BPH can be defined as an enlargement of transitional (or periurethral)
prostatic zone associated to a nodular, androgen-dependent, tissue remodelling that involves
both epithelium and fibromuscular stroma [Price et al. (1990); Lee & Peehl (2004);
Roehrborn (2008)]. Compared with the normal prostate tissue, hyperplastic nodules are
characterized by reduced epithelium-to-stroma ratio, determined by an imbalance between
growth and death programmes of stromal cells [Ishigooka et al. (1996); Claus et al. (1997);
Lin et al. (2000)], leading to increased final stromal volume. Histological micronodular
alterations appear early in young men, characterized by an immature mesenchyme displaying
features of embryonic mesenchyme, able to differentiate into myofibroblasts and smooth
muscle cells to generate a reactive stroma [Lee & Peehl (2004); Peehl & Sellers (1997);
Rumpold et al. (2002); Untergasser et al. (2005)]. These changes in stromal architecture and
homeostasis, and in the microenvironment of prostatic stromal-epithelial cell interactions,
induce subsequent epithelial rearrangements and BPH progression [McNeal (1990);
Donjacour & Cunha (1991); Bierhoff et al. (1997)].
During foetal and adult life, prostate development and trophism are regulated both directly
and indirectly by androgens [Roehrborn (2008)]. Testosterone and its metabolite
dihydrotestosterone (DHT), locally generated by the enzymatic activity of 5-reductase type
II, promote prostate cells growth and differentiation by two different mechanisms: the
ligation of the androgen receptor (AR), expressed by epithelial and stromal cells, and the
induction of stromal synthesis of growth factors, that act on epithelial and stromal
compartments in a paracrine and an autocrine manner respectively [Lee & Peehl (2004);
Roehrborn (2008)]. Among these intrinsic factors, a crucial role in embryological
differentiation and prostatic branching is exerted by fibroblast growth factors (FGFs),
transforming growth factor (TGF) and insulin-like growth factors (IGFs), which are all
markedly increased in hyperplastic glands. In particular, they have been proved to reawaken
prostatic developmental programmes normally repressed in adult life [Lee & Peehl (2004);
Roehrborn (2008); Mori et al. (1990), Barni et al. (1994); De Bellis et al. (1998); Planz et al.
(1999); Ropiquet et al. (1999); Crescioli et al. (2000); Eaton (2003)]. The most represented
FGFs in prostate are FGF-2 and FGF-7 (or keratinocyte growth factor, KGF). FGF-2 is
actively synthesized by stromal and epithelial prostate cells, which express also its specific
receptor FGFR1 [Sherwood et al. (1992); Deshmukh et al. (1997); Story et al. (1989); Boget
et al. (2001)]. It acts as an autocrine inducer of stromal proliferation, able to maintain
mesenchymal homeostasis in normal prostate and to promote the structural remodelling
typical of BPH at the earliest stages [Mori et al. (1990); Janssen et al. (2000)]. It has been
also proposed that an oestrogenic stimulation of the prostate secondary to the age-related
decline of testosterone to oestrogens ratio may lead to reactivation of tissue growth, with a
preferential proliferation of prostate stromal cell [see Prins & Korach (2008) for review].
The highest incidence of BPH in the elderly men, whose levels of circulating testosterone
progressively decrease by ageing, suggests that the local production of these mitogens is
regulated by other mechanisms besides sexual hormones. A major player in the pathogenesis
of prostate overgrowth appears to be glandular inflammation [Kramer et al. (2002, 2007);
Sciarra et al. (2007)], joining the static (mechanical urethral obstruction by prostatic
adenoma) and dynamic (detrusor hypertrophy and bladder neck smooth muscle failure)
components in LUTS development [Nickel (1994)]. The aim of this review was to overview
the cell types and molecular mediators involved in immuno-mediated inflammatory reactions
that characterize BPH onset and clinical progression. The use of vitamin D receptor (VDR)
agonists in the modulation of intraprostatic inflammatory processes, extensively analysed by
our groups, highlight new therapeutic perspectives potentially able to target multiple
pathogenetic components in BPH.
Chronic inflammation and BPH
The association between BPH and intraprostatic inflammation was first proposed based on
the histological coexistence of hyperplastic nodules and chronic inflammatory infiltrates in a
high proportion of BPH tissues [Nickel (1994); Odunjo & Elebute (1971); Kohnen & Drach
(1979); Theyer et al. (1992); Bedalov et al. (1994); Steiner et al. (1994); Nickel et al. (1999);
Di Silverio et al. (2003); Nickel et al. (2007);Sciarra et al. (2008)]. Accordingly, symptoms
suggestive of prostatitis and LUTS frequently overlap in BPH patients [Nickel (2006)]. The
importance of inflammatory reactions in the pathogenesis and evolution of BPH symptoms
was also confirmed by the demonstration of a positive correlation between a history of
young-onset prostatitis and later development of LUTS [Sutcliffe et al. (2005)]. On the other
hand, an inverse correlation between the daily use of non-steroidal anti-inflammatory drugs
and the clinical condition worsening has been detected [St Sauver et al. (2006)]. In addition,
several epidemiological studies evidenced that acute or chronic inflammation contributes to
the clinical progression of BPH-related symptoms. Results from the MTOPS trial indicate
that inflamed glands have larger volumes than non-infiltrated ones, and predispose patients to
a higher risk of unfavourable outcomes, such as AUR [McConnell et al. (2003)]. Similarly, in
a subgroup of randomly-selected patients from the REDUCE trial the association between
inflammation and severity of BPH symptoms has been described [Nickel et al. (2007)].
The intraprostatic immune system
The prostate, long considered an immunoprivileged organ [Whitmore & Gittes (1977)], is an
immunocompetent site, thanks to the presence of an intraglandular immune system that takes
part in the maintenance of reproductive tract sterility and in the prevention of autoimmune
reactions towards intraprostatic and sperm antigens [Shortliffe et al. (1981); Vykhovanets
et al. (2005)]. In the normal prostate, infiltrating leucocytes are localized within the
interstitium around epithelial ducts and between epithelial cells and consist of mast cells, T
lymphocytes (with a prevalence of CD8+ cytotoxic cells on CD4+ helper cells), macrophages
and B lymphocytes [Theyer et al. (1992); Steiner et al. (1994)]. T lymphocytes populate the
gland about the 12th week of foetal life, then their number decreases after the 30th week and
increase again with age during adult life, in the absence of any pathological alteration of
prostate histology [Theyer et al. (1992); Steiner et al. (2003)]. In BPH tissues, intraprostatic
leucocytes organize in nodular infiltrates characterized by specific phenotypic and functional

features. Based on their anatomic localization within the gland, they can be classified as
glandular, periglandular and stromal [Theyer et al. (1992)]. Among those, the periglandular
pattern is the predominant one [Theyer et al. (1992)], without a clear correlation between
inflammation pattern and histopathological inflammatory degree [Nickel et al. (1999)]. The
majority of infiltrating leucocytes are chronically activated T lymphocytes, with a reversal of
the CD8+-to-CD4+ ratio compared with the normal prostates [Theyer et al. (1992); Steiner
et al. (2003)].
Based on their cytokine expression pattern, activated CD4+ cells can be phenotipically
distinguished in three distinct effector lineages: Th1 cells, whose prototypical cytokines are
IFN and IL-2, able to regulate the cell-mediated immune response towards intracellular
pathogens; Th2 cells, that produce mainly IL-4, IL-13 and IL-5 and activate humoral
immunity, mast-cell degranulation, eosinophil influx and the immediate hypersensitivity
response; and Th17 cells, secreting IL-17 and IL-21 and involved in host defence against
extracellular pathogens and in the induction of autoimmunity [Rautajoki et al. (2008)]. IL-12
family cytokines (IL-12, IL-23 and IL-27) are primarily involved in promoting the
differentiation of naive CD4+ T cells in the different effector subsets. In particular, IL-12
induces Th1 cytokines, while IL-23 is critical for Th17 cell expansion and stabilization
[Beadling & Slifka (2006)]. Initial pathological BPH stages are characterized by the
prevalence of a Th1 response, as shown by the 3-fold increase in IFN mRNA expression and
the novel expression of IL-2 mRNA compared with the normal prostate and confirmed by the
characterization of tissue-derived T cells [Steiner et al. (2003); Kramer et al. (2003)]. During
BPH progression, IFN expression increases with a simultaneous rise in IL-4 and IL-13,
suggesting the involvement of both Th1 and Th2 responses in advanced hyperplastic tissue
inflammation [Steiner et al. (2002)].
Prostatic cells as inducers and targets of chronic inflammation
The involvement of prostate cells in the priming and progression of immune responses has
been initially suggested based on epithelial and stromal cell expression of several TLRs and
by LPS-induced up-regulation of IL-1 and IL-15 gene expression [Kramer & Marberger
(2006)]. BPH epithelial cells can acquire the ability to express class II MHC molecules
[Theyer et al. (1992); Kramer et al. (2003)]. This finding, together with TLR-4, TLR-5, TLR7 and TLR-9 over-expression, suggests a key role of epithelial cells in the induction of
immune-mediated inflammatory processes and cytokine secretion [Konig et al. (2004)].
In a recent study, we have demonstrated that human stromal prostatic cells actively contribute
to the organ-specific inflammatory process by acting as targets of bacterial or viral TLR
agonists and as antigen-presenting cells able to activate antigen-specific CD4+ T cells [Penna
et al. (2009b)]. TLR activation in BPH cells leads to the production of proinflammatory
cytokines (IL-6) and of chemokines (IL-8 and CXCL10) able to recruit infiltrating cells
[Penna et al. (2009b)]. Human stromal prostatic cells express class II MHC and costimulatory molecules (CD80, CD86, CD40, CD134L) which are strongly up-regulated by
inflammatory stimuli [Penna et al. (2009b)]. Expression of MHC class II and costimulatory
molecules enables BPH cells to activate alloantigen-specific CD4+ T lymphocytes via MHC
class II-dependent antigen presentation, showing for the first time the capacity of BPH
stromal cells to act as antigen presenting cells (APCs), inducing and sustaining pathogenic
immune responses [Penna et al. (2009b)]. Moreover, BPH cells exhibit another key feature of
APCs: production of high levels of IL-12 and IL-23 [Penna et al. (2009b)], cytokines directly
involved in committing or amplifying the differentiation of pathogenic T cells [Beadling &
Slifka (2006)].
A prostatic network of proinflammatory cytokines
This complex proinflammatory microenvironment is closely related to BPH stromal

hyperproliferation, resembling the myofibroblast-based reactive stroma and the extracellular
matrix remodelling observed in wound healing repair processes in most fibrotic diseases
associated with inflammation [Wynn (2004)] and in intraepithelial or well-differentiated
prostate cancer foci [Ayala et al. (2003)]. Stromal cells from normal prostate do not respond
to IL-2, IL-7 or IFN, but IL-4 dose-dependently inhibits their proliferation. Conversely,
polyclonal BPH stromal cell lines show an increased IL-2/IL-7/IFN-mediated growth, not
reverted by IL-4 treatment [Kramer et al. (2002)]. Even the proliferation of BPH epithelial
cells is stimulated by IFN [Deshpande et al. (1989)] and when treated with IL-1 or IL-8
they secrete KGF and FGF-2 respectively [Giri & Ittmann (2000, 2001)]. Collectively, these
observations suggest that the inflammation-induced damage of the prostatic tissue represents
a chronic process of wound healing which activates hyperproliferative programmes resulting
in BPH nodules.
Besides IFN and IL-2, an important cytokine in the generation and maintenance of
intraprostatic infiltrates is IL-15, a regulator of lymphocyte homeostasis, proliferation and
migration [Wilkinson & Liew (1995)]. IL-15 is constitutively expressed by normal prostate
cells and is predominantly restricted to the smooth muscle component, as its receptor (IL15R) [Handisurya et al. (2001)]. Increased levels of both IL-15 and IL-15R mRNA in the
luminal secretory epithelium of BPH samples, probably due to the paracrine action of T cellderived IFN, result in lymphocytic recruitment and activation [Handisurya et al. (2001)].
Another important player in the establishment of prostatic inflammation is IL-17, a T
lymphocyte-derived cytokine whose levels are negligible in normal prostate but highly
increased in BPH tissues, where it is primarily expressed and secreted by activated T
lymphocytes, epithelial and smooth muscle cells [Steiner et al. (2003)]. IL-17 plays a
predominant role in the pathogenesis and maintenance of immune responses because of its
hierarchical regulation of the proinflammatory network, exerted through several mechanisms:
induction of IL-6, IL-8 and IL-1 gene expression in epithelial, endothelial and stromal cells
[Steiner et al. (2003); Konig et al. (2004); McKenzie et al. (2006)]; triggering of IFN,
TNF, IL-10 and IL-5 release by BPH T cells [Steiner et al. (2003)]; and up-regulation of
macrophagic and epithelial levels of cyclooxygenase 2 (COX-2) [Wang et al. (2004)].
Interestingly, IL-17-mediated cytokine and chemokine production is higher than that induced
by other inflammatory stimuli, as LPS or the protein kinase activator PMA [Vykhovanets
et al. (2005)]. Hence, IL-17 can be considered a local fine tuner of BPH immune responses,
through the maintenance of the inflammatory microenvironment and the amplification of

prostatic tissue damage by oxidative stress.
Finally, the stromal production of IL-6 and IL-8 is induced in vitro by chemical, microbial
and cytokine stimuli [Steiner et al. (2002)]. IL-6 is a cytokine with pleiotropic actions
involved in acute phase reactions, haematopoiesis, antigen-specific immune responses, bone
metabolism and neural development, produced by immune (activated T and B lymphocytes,
macrophages and monocytes) and non-immune cells (fibroblasts, endothelial cells, stromal
cells and cancer cells) [Steiner et al. (2002)]. In normal and neoplastic prostate tissues, IL-6,
secreted by basal epithelial cells, represents a potent autocrine growth factor [Giri et al.
(2001)]. Its proliferative action, together with its expression in stromal and luminal epithelial
BPH cells [Royuela et al. (2001)], suggests that it may represent a major player in IL-17dependent BPH-associated inflammatory processes.
Similarly to IL-6, IL-8 is secreted by several cell types, like monocytes, activated T
lymphocytes, neutrophils, eosinophils, fibroblasts, synovial cells, adipocytes, endothelial
cells, epithelial cells and keratinocytes [Steiner et al. (2002)]. Its primary role in the
recruitment of neutrophils into inflammatory sites, in their activation and in the regulation of
their immunomodulatory properties [Kobayashi (2008)] is accompanied by a chemoattractant
activity on basophils and T cells and by a potent proangiogenetic action [Proost et al. (1996)].
Thus, this chemokine is crucially involved in many inflammatory diseases, as psoriasis
[Numerof & Asadullah (2006)], rheumatoid arthritis [Paradowska et al. (2007)],
inflammatory lung [Pease & Sabroe (2002)] and bowel diseases [MacDermott, 2007],
atherosclerosis [Braunersreuther et al. (2007)] and gastritis [Naito et al. (2005)]. In the
human prostate, IL-8 is produced in vitro and in vivo by several normal and cancerous cell
lines and is five-fold up-regulated in peripheral blood lymphocytes from patients with
prostatic carcinoma [Waugh & Wilson (2008)]. Moreover, IL-8 is highly expressed in BPH
specimens [Konig et al. (2004)] and appears to be actively involved in BPH pathogenesis.
Indeed, IL-8 stimulates stromal and epithelial overgrowth, by directly promoting the
proliferation of senescent epithelial cells [Castro et al., (2004)] and the stromal acquisition of
a myofibroblast reactive phenotype [Schauer et al. (2008)] and by indirectly inducing FGF-2
secretion [Giri & Ittmann (2001)]. Its importance in prostatic chronic inflammation is
indicated by the increased IL-8 seminal plasma levels in chronic prostatitis/chronic pelvic
pain syndrome (CP/CPPS) and in BPH patients and by their positive correlation with
symptom score and serum prostatic specific antigen (PSA), identifying IL-8 as a reliable
surrogate marker of prostatic inflammatory diseases [Penna et al. (2007)].
As we have recently demonstrated [Penna et al. (2009b)], IL-8 expression in BPH tissues
may be ascribed not only to epithelial but also to stromal cells, with a functional role in
recruiting leucocytes expressing CXCR1 and CXCR2 IL-8 receptors. The stimulation of BPH
stromal cells with Th1- and Th17-derived cytokines induces the secretion of IL-8, IL-6 and
CXCL-10, a chemokine recruiting to inflammatory sites several immune cells, in particular
Th1 lymphocytes. IL-8 directly promotes BPH stromal cell proliferation in an
autocrine/paracrine manner [Penna et al. (2007, 2009a)], with a maximal effect comparable
with T and the IGF-1 analogue Des(1-3)IGF-1 [Penna et al. (2009a)]. Therefore, IL-8 may
represent a link between stromal-induced immune responses, maintenance of chronic
inflammation and overgrowth of BPH tissues (Fig. 1).
Figure 1. IL-8 is actively involved in benign prostatic hyperplasia (BPH)-associated chronic
inflammation and mediates epithelial and stromal cell proliferation. In BPH tissues, epithelial
and stromal cells actively secrete the proinflammatory chemokine IL-8 in response to
different stimuli, including the proinflammatory cytokines IFN and IL-17 produced by
prostate-infiltrating Th1 and Th17 cells respectively. IL-8 recruits to the prostate
lymphomononuclear cells expressing the cognate receptors CXCR1 and CXCR2, promotes
both directly (through an autocrine/paracrine action) and indirectly (through the induction of
fibroblast growth factors (FGFs)-2) prostate cell proliferation. Therefore, IL-8 appears to
represent a key link between chronic inflammation and overgrowth of BPH tissues.
Aetiology of BPH inflammation
The primary event in the activation of the inflammatory network that leads to BPH tissue
remodelling is still unclear, but the infective hypothesis is a plausible one. Several studies
have demonstrated the presence of a heterogeneous set of bacterial and viral strains in BPH
samples [Sciarra et al. (2007)]. In addition, TLR agonists have been found to induce
production of proinflammatory cytokines and chemokines by BPH stromal cells, able to
recruit infiltrating cells and to promote prostate cell growth [Penna et al. (2009b)].
BPH-associated immune responses may be also triggered by self-antigens. Zisman et al.
(1995) proved the existence of a direct relationship between the immune response and the
pathogenesis of BPH by detecting anti-PSA antibodies in sera from BPH patients, concluding
that BPH could be considered an organ-limited autoimmune condition characterized by the
absence of a polyclonal B-cell activation. This hypothesis is further supported by the
prevalence of Th1 and Th17 subsets, typical of autoimmune diseases [Harrington et al.
(2006)], in BPH tissues. As CP/CPPS is eight times more frequent than bacterial prostatitis,
autoimmune responses could represent a major cause of prostatic inflammatory diseases
[Krieger et al. (2008)].
Neurological, hormonal and/or immunological dysfunctions have been proposed to influence
CP/CPPS pathogenesis [Pontari & Ruggieri (2008)]. So far, ongoing infection from any
sexually transmitted organisms has failed to be identified in those patients [Weidner et al.
(1991)], but a dysregulation of proinflammatory and anti-inflammatory cytokines has been
suspected to sustain inflammation from normal prostate bacterial flora [see Pontari &
Ruggieri (2008) for review]. Moreover, an increased nerve fibre density, the sensory
neuropeptide calcitonin gene-related peptide and a progressive mast cell degranulation with a
massive release of nerve growth factor strictly correlate with pain in CP/CPPS and may be
implicated in neurogenic inflammation and central sensitization [see Pontari & Ruggieri
(2008) for review].
Among sex hormones, the age-related decline of testosterone to oestrogens ratio has been
recognized as an important factor in the development of chronic prostatitis. In fact, short-term
administration of oestrogens at pregnancy levels was shown to induce an inflammatory
response specific to the lateral prostate of the castrated male rats, histologically similar to a
spontaneous non-bacterial prostatitis [Robinette (1988)] and associated with the increased
transcript levels of IL-1, IL-6 and macrophage inflammatory protein-2 [Harris et al. (2000)].
Conversely, the co-administration of testosterone with oestradiol prevented oestrogeninduced prostatitis, while DHT was less effective [Naslund et al. (1986)]. This finding,
together with the possible beneficial effect seen with the 5-reductase type II inhibitor
finasteride for CP/CPPS [Nickel et al. (2004)], suggests a protective role of testosterone
against inflammation independent from its conversion to DHT. Otherwise, oestrogens have
been proved to exert a critical role in the control of the immune system [see Straub (2007) for
review]. It has been proposed that the age-dependent gradual disappearance of androgens and
the simultaneous increase in oestrogens induce a weakening of the immune system, by
decreasing the activity of a population of suppressor cells that actively induce and maintain
tolerance to prostatic antigens [Kramer et al.(2007); Nickel (2008)]. Nowadays, it is well
established that the uncontrolled proliferation of prostate cells induced by chronic
inflammation is closely linked to initiation and neoplastic progression. In fact, inflammatory
infiltrates and proliferative inflammatory atrophy (PIA) are commonly described adjacent to
high-grade prostatic intraepithelial neoplasia (PIN) or early cancer, as a result of regenerative
hyperproliferative process consequent to cell injury [De Marzo et al. (2007)]. As the
activation of the isoform of the oestrogen receptor (ER) has been hypothesized to promote
prostate carcinogenesis, metastasis and perhaps androgen independence [see Prins & Korach
(2008), De Marzo et al. (2007) and Sciarra et al. (2008) for review] and the
oestrogens/androgens balance is still a crucial factor in the regulation of immune and
inflammatory responses, oestrogens seem to be a suitable candidate for the pathogenesis of
prostate cancer by stimulating the expression of genes involved in prostate inflammation and
proliferation [see Ho et al. (2004) for review]. In this view, an APC role of prostate stromal
cells similar to those observed in BPH could contribute to the hormonal stimulation of
chronic inflammation proposed to be involved in prostate carcinogenesis through the
oestrogen-induced local production of immuno-regulatory factors. Therefore, a tissue damage
consequent to oxidative stress, hypoxia, infections (urinary and/or sexually transmitted) or
autoimmunity, could trigger a stromal-driven immuno-mediated inflammatory reaction,
supported and/or amplified by endocrine-immune interactions and resulting in the release of
increased progrowth cytokines, the generation of reactive oxygen species-induced DNA
damage and neovascularization [Sandhu (2008)].
The intraprostatic reflux of urine, possibly because of an increased intraprostatic pressure
secondary to a frequent or prolonged contraction of urethra and bladder neck smooth muscle
and of prostatic stroma, may also lead to CP/CPPS [Takechi et al., 1999)]. Indeed, CP/CPPSrelated symptoms have been demonstrated to correlate with the concentration of urate or
creatinine in the expressed prostatic secretion [Persson & Ronquist (1996)], which may
produce a chemical or osmolar injury to the prostate tissue starting the immuno-mediated
inflammatory reactions.
Finally, the isolation of autoreactive CD4+ and CD8+ T lymphocytes specific for prostatic
antigens from normal individuals [Corman et al. (1998)], the capacity of seminal plasma
[Alexander et al. (1997); Batstone et al. (2002)] and specific prostate antigens [Ponniah et al.
(2000); Motrich et al. (2005)] to induce proliferation of peripheral blood mononuclear cells
(PBMCs) and CD4+ T cells, and the self-reactive CD4+ cell-mediated activation of plasma
cells (with production of high-titre autoantibodies to prostatic proteins) [Dunphy et al.
(2004)] support autoimmune responses to prostate antigens. The predominant role of
autoimmunity in CP/CPPS development has been further confirmed by several murine
models of age-related spontaneous and antigen-induced experimental autoimmune prostatitis
(EAP) [Vykhovanets et al. (2007)].
These experimental findings, together with the induction of pathogenic T cell responses by
BPH cells [Penna et al. (2009b)], suggest common mechanisms promoting and sustaining
BPH and CP/CPPS and, in our view, support the emerging theory that BPH may be
considered an asymptomatic inflammatory prostatitis. However, the lack of or a weak
correlation between inflammation and infection with severity of symptoms implies that
factors other than inflammation and infection contribute to symptoms associated with
CP/CPPS [Nickel (2008)].
In conclusion, bacterial and non-infectious chronic prostatitis, which unlike BPH affect men
of all ages [Krieger et al. (2008)], could be considered the pathogenetic background of
hyperproliferative cellular pathways, possibly as a consequence of autoimmune responses
against self-antigens released following tissue injury [Kramer & Marberger (2006)]. Among
self-antigens candidates, PSA has been recently demonstrated to be able to activate CD4+ T
cells from patients with granulomatous prostatitis, through the recognition of two different
antigenic HLA-DRB*1501-restricted peptides [Alexander et al. (2004); Klyushnenkova et al.
(2005)]. PSA antigenicity may be related to the completion of prostate development only at
puberty, or to the impairment of cellular tolerance processes by age or by hormonal changes
in the ageing male [Kramer & Marberger (2006)]. The hypothesis that the prostatic system is
able to induce and sustain intraglandular autoimmune reactions is supported by our in vitro
observations that alloreactive CD4+ T cells activated by BPH stromal cells markedly upregulate secretion of IL-12 and IL-23 by BPH cells, which could trigger and amplify the
differentiation of pathogenetic Th1 and Th17 cells [Penna et al. (2009b)] (Fig. 2).
Figure 2. Benign prostatic hyperplasia (BPH) stromal cells are inducers and targets of
prostatic chronic inflammation. BPH stromal cells express Toll-like receptors (TLRs), which
recognize structural components highly preserved among pathogens and class II major
histocompatibility complex (MHC) molecules. TLRs activation by an infectious stimulus
(bacteria, viruses or fungi) leads to the production by stromal BPH cells of proinflammatory
cytokines (IL-6) and chemokines (CXCL10 and IL-8) able to recruit infiltrating cells and to
promote prostate cell growth in an autocrine/paracrine manner. BPH stromal cells are also
able to function as non-professional antigen presenting cells (APCs) leading to the activation
of infiltrating CD4+ T lymphocytes and promoting their differentiation in Th1 and Th17
effector cells by secretion of IL-12 and IL-23 respectively. In turn, activated Th1 and Th17
lymphocytes produce proinflammatory cytokines, such as IFN and IL-17, sustaining and
amplifying immuno-mediated inflammatory responses.
VDR agonists in BPH treatment

Vitamin D production and metabolism
Vitamin D metabolites are fat-soluble secosteroid hormones synthesized for the most part
(90%) by the sequential action of solar ultraviolet radiation on the skin precursor 7dehydrocholesterol, which results into cholecalciferol (vitamin D3) formation, and the
combined hydroxylative enzymatic activities of liver and kidney to produce the principal
circulating metabolite 25(OH)D3 and the active form 1,25(OH)2D3, or calcitriol respectively.
The remaining 10% of vitamin D3 derivates are generated from diet cholecalciferol and
ergocalciferol (vitamin D2) [Anderson et al. (2004)]. The biological effects of calcitriol are
mediated by its high affinity binding to the VDR, a member of nuclear receptor transcription
factors superfamily. Its ligand-dependent conformational changes promote heterodimerization
with the retinoid X receptor (RXR) at vitamin D-responsive elements (VDREs) of target
genes, and recruitment of receptor corepressor and coactivator proteins. This transcriptional
complex induces intrinsic histone-modifying activities and direct recruitment of key
transcription initiation components at regulated promoters. This molecular interaction results
in chromatin remodelling, RNA polymerase II-mediated transcription rate regulation and
modulation of target gene expression [Jones et al. (1998); Carlberg & Polly (1998)]. A wellknown biological activity of the vitamin D system is regulation of calcium and phosphorus
metabolism [DeLuca (2004)]. More recently, VDR agonists have been found to possess antiangiogenetic effects, anti-proliferative and pro-differentiating actions [Napgal et al. (2005)],
as well as anti-inflammatory and immunoregulatory properties [Adorini & Penna (2008)].
Vitamin D and its analogs in prostatic diseases
A link between the vitamin D system and the prostate was first established by
epidemiological correlation of increased prostate cancer incidence and mortality rates with
vitamin D insufficiency [Schwartz (2005)]. The prostate was then recognized as an extrarenal
site of vitamin D synthesis and action through the expression of 1-hydroxylase and VDR
respectively [Ali & Vaidya (2007)]. VDR expression in tissues derived from the urogenital
sinus, as prostate and bladder, is quantitatively similar to the classic target organs for
calcitriol, as liver, kidney, and bone, although lower than in the bowel and in malignant
prostate or bladder cell lines [Maggi et al. (2006)]. Moreover, a growth-regulating role of
calcitriol synthetized by the prostate is suggested by the demonstration of in vitro and in vivo
anti-proliferative, prodifferentiative, proapoptotic and anti-invasive properties in several
models of prostate cancer [Ali & Vaidya (2007)], and by a marked decrease of 1hydroxylase activity in prostate cancer cell lines [Maggi et al. (2006)].
Based on these preclinical results, the chemotherapic efficacy of calcitriol, alone or in
association with classical anti-tumoral drugs (dexamethasone, docetaxel, carboplatin and
estramustine), was tested in several clinical trials in prostate cancer patients [Harzstark &
Ryan (2008)]. The main limitation to the clinical use of calcitriol is represented by its
hypercalcaemic side effects, which some therapeutic protocols tried to overcome by an
intermittent drug administration [Beer et al. (2005); Trump et al. (2006); Beer et al. (2008)].
The chemical synthesis of vitamin D non-hypercalcaemic analogs, characterized by a
therapeutic window higher than calcitriol [Napgal et al. (2005)], has led to the synthesis of
more than 2000 different molecules, some of them approved for the treatment of specific
diseases like psoriasis, secondary hyperparathyroidism or osteoporosis [Pinette et al. (2003)].
Pharmacological management of BPH is a novel application of vitamin D analogs, prompted
by the detection of VDR expression in cultured prostatic and bladder stromal cells derived
from BPH patients [Maggi et al. (2006)]. Reducing prostate overgrowth by decreasing intraprostatic androgen signalling, without directly interfering with systemic androgen action,
would obviate the adverse systemic side effects of anti-androgens, such as 5-reductase
inhibitors. In addition, VDR agonists display marked anti-inflammatory properties and this
class of agents could therefore represent an interesting therapeutic option for the
pharmacological treatment of BPH [Maggi et al. (2006)].
VDR agonists treat BPH-associated luts
Preclinical studies performed in our laboratory have shown reduced growth and survival of
primary BPH stromal cells by two non-hypercalcaemic VDR agonists, BXL-353 and BXL628 (elocalcitol) [Maggi et al. (2006)]. In particular, elocalcitol, which is more potent than
BXL-353, decreased testosterone-induced BPH cell proliferation to a similar extent than
finasteride and cyproterone acetate, prompting apoptosis even in presence of intraprostatic
growth factors and completely antagonizing the effect of androgenic stimulation at
subpicomolar concentrations. However, this anti-androgenic action is not exerted through a
direct interference with the AR signalling, as elocalcitol does not modify 5-reductase type I
and II activity, and does not bind the AR or affects its transcriptional activity [Crescioli et al.
(2004)]. Therefore, we hypothesized that molecular mechanisms involved in the antiproliferative and pro-apoptotic effects of VDR agonists in BPH cells might operate
downstream the AR. Evidence supporting this hypothesis includes decreased
autophosphorylation of KGFR and IGF1R, arrest of cell cycle progression at G1, with a
parallel increase in clusterin expression and decreased expression of anti-apoptotic factor bcl2, which is positively modulated by androgens and KGF [Crescioli et al. (2004)].
Elocalcitol significantly decreased prostate growth both in unmanipulated and in castrated Treplaced rats, with an effect comparable with finasteride but without affecting testis
androgenic secretion or pituitary function [Crescioli et al. (2004)]. Interestingly, both
prostatic epithelial and stromal cells from elocalcitol-treated rats showed increased apoptotic
rate and clusterin expression, confirming in vitro observations [Crescioli et al. (2004)]. As
rats do not develop BPH spontaneously, the anti-hyperplasic potential of elocalcitol was
tested in male beagle dogs chronically treated for 9 months with 5 g/kg/die. In this model,
we observed a reduction of prostate weight, more evident after a 2-month recovery,
suggesting a prolonged pharmacological activity of this compound, in the absence of side

effects [Adorini et al. (2007)].
These preclinical data prompted a 12-week phase IIa, multicentre, double-blind, randomized,
placebo-controlled clinical trial aimed at evaluating the efficacy and safety of elocalcitol
administration (150 g/die) in BPH patients [Colli et al. (2006)]. Elocalcitol exhibited a 7.2%
reduction in prostate volume, measured by pelvic MRI, compared with the placebo.
Importantly, 92% of elocalcitol-treated patients did not experience a clinically significant
growth in prostate volume compared with 48% in the placebo group. Thus, the reduction of
prostate volume in elocalcitol-treated group against its marked increase in the placebo group
indicates the ability of this VDR agonist to block the ongoing BPH process. During the trial,
no difference was observed in symptom score or urodynamic parameters, probably because of
the short duration of this proof-of-concept study and because patients were not screened for
symptoms but only for prostatic volume [Colli et al. (2006)].
To elucidate this point, a 6-months phase IIb study was performed to measure maximum
urinary flow rate and symptom severity as secondary end-points in patients with at least
moderate symptomatology. Elocalcitol was effective in improving maximum urinary flow
rate (Qmax) and ameliorating LUTS, as well as arresting prostate growth and preventing the
risk of AUR and need for surgery [Montorsi & Colli (2008)], all key parameters of BPH
progression. Given the poor correlation between LUTS and prostate size particularly in early
phases of BPH development, the mechanisms underlying their improvement may be referred
to a direct effect of elocalcitol on bladder musculature and the dynamic component of LUTS
pathogenesis [Crescioli et al. (2005); Morelli et al. (2007)].
Urethral obstruction determined by the hyperplastic prostate is compensated in the earliest
stages by a bladder wall hypertrophy and an increased muscle contractile activity. Later on,
the bladder smooth muscle becomes dysfunctional, with more frequent spontaneous nonvoiding contractions and a reduced ability to generate efficient voiding pressure. As
anticholinergic drugs, first line treatment for overactive bladder, induce unpleasant side
effects (dry mouth, constipation, tachycardia and central nervous system symptoms) due to
their incomplete selectivity [Andersson (2004)], alternative therapeutic strategies are sought.
VDR agonists reduce human bladder cell growth, induce apoptosis and regulate smooth
muscle phenotype remodelling, by decreasing the expression of activated myofibroblast
markers such as desmin and smoothelin [Crescioli et al. (2005)].
Consistent with the role of RhoA/ROCK signalling in regulating human and rat bladder
contraction and tone, in particular in generating involuntary contractions [Peters et al.
(2006)], we have demonstrated that elocalcitol affects bladder contractility via inhibition of
the calcium sensitizing RhoA/ROCK pathway by interfering with RhoA activation [Morelli
et al. (2007)]. The reduction of RhoA/ROCK-mediated inappropriate bladder contraction
induced by elocalcitol does not interfere with the overall detrusor motility, preventing urinary
retention due to voiding impairment. In conclusion, our results indicate possible beneficial
effects of elocalcitol on bladder overactivity by two mechanisms: counteracting the enhanced
expression and signalling of growth factors involved in bladder smooth muscle hypertrophy
and hyperplasia [Crescioli et al. (2005)], and increasing the contractile efficiency of bladder
muscle cells through the modulation of smooth muscle gene expression and the downregulation of smooth muscle myofilament sensitization to calcium [Morelli et al. (2007)].
Based on these preclinical premises, a phase IIa, double blind, placebo-controlled study has
shown clear efficacy signals on the primary end-point (mean volume voided per micturition)
and on symptoms, including frequency, nocturia and incontinence episodes [Colli et al.
(2007)]. A multi-centre phase IIb trial is currently ongoing.
Immunomodulatory properties of VDR agonists
Immunomodulatory properties of VDR agonists were investigated after the discovery of VDR
expression in most cell types of the immune system, in particular in APCs (macrophages and
dendritic cells) and T lymphocytes [Adorini & Penna (2008)]. Major target cells of VDR
agonists are APCs and T lymphocytes, whose activity is affected both directly and indirectly,
via modulation of APC activation. Several key cytokines in T lymphocytes have been shown
to be targeted by VDR ligands, in particular Th1-type cytokines, whose secretion is directly
inhibited with a resulting selective inhibition of pathogentic effector T cell development
[Adorini & Penna (2008)]. Calcitriol has also been shown, under appropriate conditions, to
enhance the development of Th2 cells via a direct effect on nave CD4+ cells and
enhancement of IL-4 transcription. The beneficial effect of VDR agonists has been
demonstrated in the prevention and treatment of several experimental autoimmune diseases,
including lupus erythematosus, experimental allergic encephalomyelitis, collagen-induced
arthritis, Lyme arthritis, inflammatory bowel diseases and type I diabetes, and also in
allograft rejection [Adorini & Penna (2008)].
A novel aspect of VDR agonists in the treatment of autoimmune diseases is provided by the
induction of CD4+CD25+Foxp3+ regulatory T cells. An important role in the
immunoregulatory activity of VDR agonists is played by their ability to markedly modulate
the phenotype and function of APCs, in particular of dendritic cells (DCs), both in vitro and
in vivo. Not only calcitriol inhibits the production of IL-12 [DAmbrosio et al. (1998)], but
vitamin D and its analogues induce monocyte- and bone marrow-derived DCs to acquire
tolerogenic properties by down-regulating the expression of CD40, CD80 and CD86, by
abrogating the IL-12 secretion and by highly enhancing IL-10 production [Adorini & Penna
(2008)]. These immunomulatory properties lead to induction of transplantation tolerance in
animal models of allograft rejection [Gregori et al. (2001); Griffin et al. (2001)]. In addition,
APCs can synthesize and secrete calcitriol because of their expression of 1-hydroxylase,
which is powerfully stimulated by IFN [Overbergh et al. (2000)]. Thus, APC-derived
calcitriol could physiologically contribute to locally regulate innate and adaptive immune
responses.
Immunomodulatory effects of VDR agonists in chronic inflammatory

prostatitis
Non-obese diabetic (NOD) mice develop experimental autoimmune prostatitis (EAP) after
immunization with mouse prostate homogenate emulsified in complete Freunds adjuvant
[Vykhovanets et al. (2007)]. Administration of elocalcitol at normocalcaemic doses in already
established EAP for 2 weeks (orally five dose/week at 100 g/kg from day 14 to 28 postimmunization) reduces by 67% the number of the intraprostatic infiltrates compared with
vehicle-treated mice. The marked decrease of intraprostatic inflammatory cell (CD4+ and
CD8+ T cells, B cells, macrophages and DCs) infiltration is characterized by a reduced
proliferation and an enhanced activation-induced cell death, effects superior to those induced
by an optimal dose of dexamethasone [Penna et al. (2006)]. The molecular effect of
elocalcitol is exerted through inhibition of CD4+ T cell responses in prostate-infiltrating cells
and in prostate-draining lymph node cells, as demonstrated by reduced ex vivo production of
IFN and IL-17 and markedly decreased expression of iNOS, a key enzyme required for the
synthesis of the inflammatory agent NO [Tinker & Wallace (2006)], and of NO itself, in
peritoneal macrophages. The inhibitory action of elocalcitol on T cell responses is also
confirmed in NOD mice immunized with prostatic steroid binding protein (PSBP) or its
immunodominant epitope PSBP2140. In addition, a reduced response to PSBP is observed in
NOD. Severe combined immunodeficiency (SCID) recipients transferred with CD4+ T cells
from elocalcitol-treated NOD mice [Penna et al. (2006)], consistent with the ability of VDR
agonists to inhibit pathogenic mechanisms in several Th1 cell-dependent autoimmune
diseases [Adorini & Penna (2008)]. Elocalcitol is able to inhibit the proliferation and to
induce the apoptosis not only of pathogenic T cells but also of epithelial and stromal prostatic
cells, suggesting a dual effect in promoting maintenance of normal glandular architecture.
Finally, the dose-response analysis of elocalcitol effect demonstrates that about 60%
reduction in the number of intraprostatic infiltrates, compared with the vehicle-treated
animals, is already obtained with 3 g/kg, a dose 30-fold lower than the maximum tolerated
dose of this compound in terms of hypercalcemia. Thus, the therapeutic window of elocalcitol
in the treatment of EAP is rather wide [Penna et al. (2006)].
Elocalcitol inhibits IL-8-dependent BPH stromal cell proliferation and
inflammatory response
We have recently demonstrated that elocalcitol inhibits IL-8 production induced by

proinflammatory cytokines secreted by prostate-infiltrating CD4+ T cells (IFN-, IL-17 and
TNF-) in human prostatic stromal cells, accompanied by reduced COX-2 expression and
prostaglandin E2 (PGE2) production, and by arrest of the nuclear translocation of the nuclear
factor-B (NF-B), a transcriptional factor which regulates also IL-8 production. IL-8
promotes BPH cell growth and elocalcitol dose-dependently counteracts IL-8-dependent BPH
cell proliferation via inhibition of the RhoA/ROCK pathway [Penna et al. (2009a)]. These
effects are consistent with the role of this calcium-sensitizing signalling in the regulation of
the inflammatory processes [Segain et al. (2003); Schmeck et al. (2003)], through the
activation of NF-B [Perona et al. (1997); Montaner et al. (1998)] and the induction of IL-8
secretion [Zhao et al. (2002, 2003)].
Therefore, these data provide a mechanistic explanation for the role of IL-8 in BPH
pathogenesis, showing that a combination of Th1 and Th17 cell-derived inflammatory
cytokines can markedly stimulate its secretion by BPH stromal cells. Moreover, our results
suggest an IL-8-dependent link bridging inflammatory response and cell proliferation in BPH
pathogenesis, which can be targeted by elocalcitol through multiple mechanisms of action.
Finally, the increased VDR expression promoted by T cell-derived inflammatory cytokines in
BPH cells renders them more susceptible to the inhibitory action of elocalcitol [Penna et al.
(2009a)].
Conclusions
Chronic inflammation can be considered the third component of BPH pathogenesis, taking
part with the AR signalling in the induction of the tissue remodelling typical of the advanced
stages of the disease. Prostatic stromal cells exert a critical role in the induction of
inflammatory responses, by activating CD4+ lymphocytes and favouring their differentiation
to the effector subsets Th1 and Th17 [Penna et al. (2009b)]. Thus, BPH can be seen as a form
of asymptomatic inflammatory prostatitis, whose pathogenesis may be triggered by infection.
The release of prostatic self-antigens following tissue damage may sensitize the immune
system and start autoimmune responses. Among proinflammatory cytokines and chemokines
produced by the prostatic microenvironment, stromal-derived IL-8 may be considered a key
link between chronic inflammation and stromal cell proliferation. The upregulation of VDR
in BPH cells after exposure to proinflammatory stimuli amplifies the anti-inflammatory
properties of the VDR agonist elocalcitol, which is able to inhibit the COX-2/PGE2 pathway,
the nuclear translocation of NF-B and the RhoA/ROCK signalling [Penna et al. (2009a)]. In
particular, the effect on this calcium sensitizing pathway may represent a common
denominator for the therapeutic efficacy of this drug on all the three components of BPH,
static, dynamic and inflammatory.
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Ringkasan
Benign prostatic hyperplasia (BPH) adalah gangguan umum yang mempengaruhi 50-80%
dari penduduk laki-laki tua. Androgen dan usia secara tradisional dianggap sebagai faktor
penentu utama dari pembesaran prostat, tetapi dalam tahun terakhir peran potensial penting
peradangan kronis pada patogenesis BPH telah muncul. Prostatitis kronis bakteri dan non
infeksi dapat mewakili faktor menghasut menyebabkan hiperproliferasi jaringan, mungkin
melalui baru ini menunjukkan antigen-presenting kapasitas sel stroma prostat,
memungkinkan mereka untuk mendorong dan mempertahankan respon imun intraglandular.
Prostat pertumbuhan mempromosikan kemokin IL-8 bisa mewakili hubungan langsung
antara peradangan prostat kronis dan proliferasi sel autokrin / parakrin stroma, dalam
perjanjian dengan sekresi ditandai yang diinduksi dalam sel stroma BPH oleh kombinasi Th1
dan Th17 sel yang diturunkan sitokin inflamasi. BPH stroma sel mengekspresikan reseptor
vitamin D (VDR), yang up-diatur oleh paparan terhadap rangsangan inflamasi. Nonhypercalcaemic VDR agonis elocalcitol, ditunjukkan untuk menangkap pengembangan BPH
dengan mengurangi sinyal intra prostat androgen tanpa langsung mengganggu kerja androgen
sistemik, diberikannya sifat immunoregulatory dan anti-inflamasi dalam patologi prostat yang
berbeda ditandai dengan pertumbuhan dan peradangan. Mekanisme aksi agonis VDR
mendukung peran penting peradangan kronis pada patogenesis BPH dan memperkuat konsep
dari agen-agen sebagai pilihan terapi untuk pengobatan farmakologi dari BPH.
Pengenalan
Benign prostatic hyperplasia (BPH) adalah neoplasma jinak yang paling sering pada pria
penuaan dan salah satu kondisi kronis yang paling umum pada populasi laki-laki, dengan
prevalensi histologis dalam otopsi dari 50% pada pria berusia 50-60 tahun dan 90% lebih dari
80 tahun [McVary (2006)]. Seperti kebanyakan penyakit kronis, BPH adalah progresif:
memerlukan waktu yang panjang untuk berevolusi dari perubahan jaringan sebelumnya untuk
onset klinis dengan gejala-gejala saluran kemih (LUT) [Jacobsen et al. (1996); Roberts et al.
(2000); Fitzpatrick (2006)], dan jika tidak diobati, sering mempersulit dengan disfungsi
kandung kemih dan hipertrofi mungkin menyebabkan retensi urin akut (AUR) [McNeal
(1990); Jacobsen et al. (1997); Kolman dkk. (1999); McConnell dkk. (2003); Roehrborn
(2006); Roehrborn dkk. (2008)].
Secara histologi, BPH dapat didefinisikan sebagai pembesaran prostat zona transisi (atau
periuretra) yang berhubungan dengan renovasi, nodular androgen-dependent, jaringan yang
melibatkan kedua epitel dan stroma fibromuskular [Harga et al. (1990); Lee & Peehl (2004);
Roehrborn (2008)]. Dibandingkan dengan jaringan prostat yang normal, nodul hiperplastik
ditandai dengan berkurangnya epitel-ke-rasio stroma, ditentukan oleh ketidakseimbangan
antara program pertumbuhan dan kematian sel-sel stroma [Ishigooka dkk. (1996); Claus et al.
(1997); Lin et al. (2000)], yang menyebabkan peningkatan volume stroma akhir. Perubahan
histologis micronodular muncul dini pada pria muda, ditandai dengan mesenkim belum
dewasa menampilkan fitur dari mesenkim embrionik, mampu berdiferensiasi menjadi
myofibroblasts dan sel otot polos untuk menghasilkan sebuah "stroma reaktif" [Lee & Peehl
(2004); Peehl & Penjual (1997) ; Rumpold dkk. (2002); Untergasser dkk. (2005)]. Perubahan
dalam arsitektur stroma dan homeostasis, dan dalam lingkungan mikro prostatic stroma-epitel
interaksi sel, menyebabkan penyusunan ulang epitel berikutnya dan BPH perkembangan
[McNeal (1990); Donjacour & Cunha (1991); Bierhoff et al. (1997)].
Selama hidup janin dan dewasa, prostat pengembangan dan trophism diatur baik secara
langsung maupun tidak langsung oleh androgen [Roehrborn (2008)]. Testosteron dan
metabolit dihidrotestosteron (DHT), lokal yang dihasilkan oleh aktivitas enzimatik 5reduktase tipe II, mempromosikan prostat pertumbuhan sel dan diferensiasi oleh dua
mekanisme yang berbeda: ligasi dari reseptor androgen (AR), yang dinyatakan oleh sel-sel
epitel dan stroma, dan induksi sintesis stroma faktor pertumbuhan, yang bekerja pada epitel
dan stroma kompartemen dalam parakrin dan secara autokrin masing-masing [Lee & Peehl
(2004); Roehrborn (2008)]. Di antara faktor-faktor intrinsik, peran penting dalam diferensiasi
embriologis dan percabangan prostat yang diberikan oleh faktor pertumbuhan fibroblast
(FGFs), mengubah pertumbuhan faktor (TGF) dan insulin-seperti faktor pertumbuhan
(IGFs), yang semuanya nyata meningkat dalam kelenjar hiperplastik. Secara khusus, mereka
telah terbukti membangunkan kembali program-program pembangunan prostat biasanya
ditekan dalam kehidupan dewasa [Lee & Peehl (2004); Roehrborn (2008); Mori et al. (1990),
Barni et al. (1994); De Bellis dkk. (1998); Planz dkk. (1999); Ropiquet dkk. (1999); Crescioli
dkk. (2000); Eaton (2003)]. Para FGFs paling terwakili di prostat adalah FGF-2 dan FGF-7
(atau faktor pertumbuhan keratinosit, KGF). FGF-2 secara aktif disintesis oleh sel stroma
prostat dan epitel, yang mengekspresikan reseptor spesifik juga FGFR1 [Sherwood dkk.
(1992); Deshmukh dkk. (1997); Cerita dkk. (1989); Boget dkk. (2001)]. Ini bertindak sebagai
induser autokrin proliferasi stroma, mampu mempertahankan homeostasis mesenchymal di
prostat normal dan untuk mempromosikan renovasi struktural khas BPH pada tahap awal
[Mori et al. (1990); Janssen et al. (2000)]. Telah juga mengusulkan bahwa stimulasi estrogen
prostat sekunder terhadap penurunan terkait usia testosteron untuk rasio estrogen dapat
menyebabkan reaktivasi pertumbuhan jaringan, dengan proliferasi sel stroma preferensial
prostat [lihat Prins & Korach (2008) untuk ditinjau ].
Insiden tertinggi BPH pada pria lanjut usia, yang tingkat sirkulasi testosteron semakin
menurun penuaan, menunjukkan bahwa produksi lokal dari mitogens diatur oleh mekanisme
lain selain hormon seksual. Seorang pemain utama dalam patogenesis prostat pertumbuhan
berlebih tampaknya peradangan kelenjar [Kramer et al. (2002, 2007); Sciarra dkk. (2007)],
bergabung dengan statis (obstruksi uretra mekanik oleh adenoma prostat) dan dinamis
(hipertrofi detrusor kandung kemih dan kegagalan leher otot polos) komponen dalam
pengembangan LUT [Nikel (1994)]. Tujuan dari kajian ini adalah untuk gambaran sel jenis
dan mediator molekuler yang terlibat dalam immuno-dimediasi reaksi inflamasi yang
mencirikan timbulnya BPH dan pengembangan klinis. Penggunaan reseptor vitamin D
(VDR) agonis dalam modulasi dari proses inflamasi intraprostatic, luas dianalisis dengan
kelompok kami, sorot perspektif terapi baru yang berpotensi dapat menargetkan komponen
patogenetik beberapa di BPH.
Kronis peradangan dan BPH
Hubungan antara BPH dan peradangan intraprostatic pertama kali diusulkan berdasarkan
koeksistensi histologis nodul hiperplastik dan infiltrat inflamasi kronis pada proporsi yang
tinggi dari BPH jaringan [Nikel (1994); Odunjo & Elebute (1971); Kohnen & Drach (1979);
Theyer et al. (1992); Bedalov dkk. (1994); Steiner et al. (1994); Nikel dkk. (1999); Di
Silverio dkk. (2003); Nikel dkk. (2007); Sciarra dkk. (2008)]. Dengan demikian, gejala yang
memberi kesan prostatitis dan LUT sering tumpang tindih dalam penderita BPH [Nikel
(2006)]. Pentingnya reaksi inflamasi dalam patogenesis dan evolusi gejala BPH juga
dikonfirmasi oleh demonstrasi korelasi positif antara riwayat muda-awal prostatitis dan
perkembangan selanjutnya dari LUT et [Sutcliffe al. (2005)]. Di sisi lain, sebuah korelasi
terbalik antara penggunaan sehari-hari non-steroid anti-inflamasi dan kondisi klinis yang
memburuk telah terdeteksi [St Sauver dkk. (2006)]. Selain itu, studi epidemiologi beberapa
dibuktikan bahwa peradangan akut atau kronis berkontribusi pada pengembangan klinis BPH
gejala terkait. Hasil dari percobaan menunjukkan bahwa kelenjar MTOPS meradang memiliki
volume yang lebih besar daripada non-disusupi orang, dan mempengaruhi pasien dengan
risiko yang lebih tinggi dari hasil yang tidak menguntungkan, seperti AUR et [McConnell al.
(2003)]. Demikian pula, dalam subkelompok pasien secara acak dipilih dari sidang
MENGURANGI hubungan antara inflamasi dan keparahan gejala BPH telah digambarkan
Nikel [et al. (2007)].
Sistem kekebalan tubuh intraprostatic
Prostat, lama dianggap organ immunoprivileged [Whitmore & Gittes (1977)], adalah situs
imunokompeten, berkat adanya sistem kekebalan intraglandular yang mengambil bagian
dalam pemeliharaan kemandulan saluran reproduksi dan dalam pencegahan reaksi autoimun
terhadap intraprostatic dan sperma antigen [Shortliffe dkk. (1981); Vykhovanets dkk. (2005)].
Dalam prostat normal, leukosit infiltrasi dilokalisasi dalam interstitium sekitar saluran epitel
dan antara sel-sel epitel dan terdiri dari sel mast, limfosit T (dengan prevalensi CD8 + sel
sitotoksik pada sel CD4 + helper), makrofag dan limfosit B [Theyer dkk. (1992); Steiner et
al. (1994)]. T limfosit kelenjar mengisi sekitar 12 minggu kehidupan janin, maka jumlah
mereka berkurang setelah minggu 30 dan meningkat lagi dengan usia pada masa dewasa,
dalam hal tidak adanya perubahan patologis prostat histologi [Theyer dkk. (1992); Steiner et
al. (2003)]. Dalam jaringan BPH, leukosit intraprostatic berorganisasi infiltrat nodular
dicirikan oleh fitur fenotipik dan fungsional tertentu. Berdasarkan lokalisasi anatomis mereka
dalam kelenjar, mereka dapat digolongkan sebagai kelenjar, stroma dan periglandular et
[Theyer al. (1992)]. Di antara mereka, pola periglandular adalah yang dominan [Theyer dkk.
(1992)], tanpa korelasi yang jelas antara pola peradangan dan inflamasi derajat histopatologi
[Nickel et al. (1999)]. Mayoritas leukosit infiltrasi secara kronis diaktifkan limfosit T, dengan
pembalikan rasio CD8 +-to-CD4 + dibandingkan dengan prostat normal [Theyer dkk. (1992);
Steiner et al. (2003)].
Berdasarkan pola ekspresi mereka sitokin, CD4 diaktifkan + sel dapat phenotipically
dibedakan dalam tiga garis keturunan efektor yang berbeda: sel Th1, yang prototipikal sitokin
adalah IFN dan IL-2, mampu mengatur respon sel-mediated imun terhadap patogen
intraseluler, sel Th2, yang memproduksi terutama IL-4, IL-13 dan IL-5 dan mengaktifkan
imunitas humoral, tiang-sel degranulasi, masuknya eosinofil dan respon hipersensitivitas
segera; dan sel Th17, mensekresi IL-17 dan IL-21 dan terlibat dalam pertahanan tuan rumah
melawan ekstraseluler patogen dan dalam induksi autoimunitas [Rautajoki dkk. (2008)].
Sitokin IL-12 keluarga (IL-12, IL-23 dan IL-27) terutama terlibat dalam mempromosikan
diferensiasi CD4 + T sel naif dalam subset efektor yang berbeda. Secara khusus, IL-12
menginduksi sitokin Th1, sedangkan IL-23 sangat penting untuk ekspansi sel Th17 dan
stabilisasi [Beadling & Slifka (2006)]. Awal patologis BPH tahap ditandai dengan prevalensi
respon Th1, seperti yang ditunjukkan oleh peningkatan 3 kali lipat dalam ekspresi mRNA
IFN dan ekspresi baru dari IL-2 mRNA dibandingkan dengan prostat normal dan
dikonfirmasi oleh karakterisasi jaringan yang diturunkan T sel [Steiner et al. (2003); Kramer
et al. (2003)]. Selama perkembangan BPH, peningkatan ekspresi IFN dengan kenaikan
simultan di IL-4 dan IL-13, menunjukkan keterlibatan tanggapan baik Th1 dan Th2 dalam
peradangan jaringan canggih hiperplastik [Steiner et al. (2002)].
Prostat sel sebagai induser dan target peradangan kronis
Keterlibatan sel prostat di priming dan perkembangan respon imun telah awalnya
menyarankan berdasarkan ekspresi sel epitel dan stroma dari TLRs beberapa LPS diinduksi
regulasi-IL-1 dan IL-15 ekspresi gen [Kramer & Marberger ( 2006)]. Sel epitel BPH dapat
memperoleh kemampuan untuk mengekspresikan molekul MHC kelas II [Theyer dkk.
(1992); Kramer et al. (2003)]. Temuan ini, bersama dengan TLR-4, TLR-5, TLR-7 dan TLR9 over-ekspresi, menunjukkan peran penting dari sel epitel dalam induksi kekebalan-mediated
proses peradangan dan sekresi sitokin [Konig dkk. (2004)].
Dalam penelitian terbaru, kami telah menunjukkan bahwa manusia sel prostat stroma secara
aktif berkontribusi pada proses organ-spesifik inflamasi dengan bertindak sebagai target dari
agonis TLR bakteri atau virus dan sebagai antigen-presenting sel mampu mengaktifkan
antigen-spesifik sel T CD4 + [Penna et al. (2009b)]. Aktivasi TLR dalam sel BPH mengarah
ke produksi sitokin pro inflamasi (IL-6) dan kemokin (IL-8 dan CXCL10) dapat merekrut
infiltrasi sel [Penna dkk. (2009b)]. Manusia sel stroma prostat mengekspresikan MHC kelas
II dan co-stimulasi molekul (CD80, CD86, CD40, CD134L) yang sangat up-diatur oleh
rangsangan inflamasi Penna et al. [ (2009b)]. Ekspresi MHC kelas II dan molekul
costimulatory memungkinkan BPH sel untuk mengaktifkan alloantigen spesifik CD4 + T
limfosit melalui MHC II yang bergantung presentasi antigen kelas, menunjukkan untuk
pertama kalinya kapasitas sel BPH stroma untuk bertindak sebagai antigen sel presentasi
(APC), merangsang patogen dan mempertahankan respon imun [Penna dkk. (2009b)]. Selain
itu, sel BPH menunjukkan fitur lain kunci dari APC: produksi tingkat tinggi IL-12 dan IL-23
[Penna dkk. (2009b)], sitokin yang terlibat langsung dalam melakukan atau memperkuat
diferensiasi sel-sel patogen T [Beadling & Slifka (2006)].
Sebuah jaringan prostat sitokin proinflamasi
Ini mikro proinflamasi kompleks terkait erat dengan hiperproliferasi stroma BPH,
menyerupai stroma myofibroblast berbasis reaktif dan renovasi matriks ekstraseluler diamati
dalam proses perbaikan luka penyembuhan pada penyakit fibrosis yang paling berhubungan
dengan peradangan [Wynn (2004)] dan dalam intraepithelial atau berdiferensiasi baik kanker
prostat fokus [Ayala dkk. (2003)]. Sel stroma dari prostat normal tidak merespon terhadap IL2, IL-7 atau IFN, tapi IL-4 dosis ketergantungan menghambat proliferasi mereka.
Sebaliknya, poliklonal BPH baris sel stroma menunjukkan pertumbuhan IL-2/IL-7/IFNmediated meningkat, belum dikembalikan oleh IL-4 pengobatan [Kramer et al. (2002)].
Bahkan proliferasi sel epitel BPH dirangsang oleh IFN [Deshpande et al. (1989)] dan ketika
diobati dengan IL-1 atau IL-8 mereka mengeluarkan KGF dan FGF-2 masing-masing [Giri
& Ittmann (2000, 2001)]. Secara kolektif, pengamatan ini menunjukkan bahwa kerusakan
yang disebabkan peradangan dari jaringan prostat merupakan proses penyembuhan luka
kronis yang mengaktifkan program hyperproliferative mengakibatkan nodul BPH.
Selain IFN dan IL-2, sebuah sitokin yang penting dalam generasi dan pemeliharaan infiltrat
intraprostatic adalah IL-15, pengatur homeostasis limfosit, proliferasi dan migrasi [Wilkinson
& Liew (1995)]. IL-15 yang konstitutif diekspresikan oleh sel prostat normal dan terutama
terbatas pada komponen otot polos, sebagai reseptor (IL-15R) [Handisurya dkk. (2001)].
Peningkatan tingkat kedua IL-15 dan IL-15R mRNA di epitel sekresi luminal sampel BPH,
mungkin karena aksi parakrin T sel yang diturunkan IFN, mengakibatkan rekrutmen
limfositik dan aktivasi [Handisurya dkk. (2001)].
Lain pemain penting dalam pembentukan peradangan prostat adalah IL-17, sebuah sitokin
limfosit yang diturunkan T yang kadarnya diabaikan dalam prostat normal tetapi sangat
meningkat pada BPH jaringan, di mana ia terutama diungkapkan dan disekresi oleh limfosit T
aktif, otot halus dan epitel sel [Steiner et al. (2003)]. IL-17 memainkan peran utama dalam
patogenesis dan pemeliharaan respon imun karena peraturan hirarki dari jaringan pro
inflamasi, yang diberikan melalui beberapa mekanisme: induksi IL-6, IL-8 dan IL-1 ekspresi
gen dalam epitel, endotel dan stroma sel [Steiner et al. (2003); Konig dkk. (2004); McKenzie
dkk. (2006)]; memicu IFN, TNFa, IL-10 dan IL-5 rilis oleh sel BPH T [Steiner et al.
(2003)], dan up-peraturan tingkat macrophagic dan epitel siklooksigenase 2 (COX-2) [Wang
et al. (2004)]. Menariknya, IL-17-dimediasi sitokin dan kemokin produksi lebih tinggi dari
yang disebabkan oleh rangsangan inflamasi lainnya, seperti LPS atau protein kinase aktivator
PMA [Vykhovanets dkk. (2005)]. Oleh karena itu, IL-17 dapat dianggap sebagai tuner baik
lokal respon kekebalan BPH, melalui pemeliharaan lingkungan mikro inflamasi dan
amplifikasi kerusakan jaringan prostat oleh stres oksidatif.
Akhirnya, produksi stroma IL-6 dan IL-8 diinduksi secara in vitro oleh rangsangan kimia,
mikroba dan sitokin [Steiner et al. (2002)]. IL-6 merupakan sitokin dengan tindakan
pleiotropic terlibat dalam reaksi fase akut, haematopoiesis, antigen-spesifik tanggapan
kekebalan tubuh, metabolisme tulang dan perkembangan saraf, yang dihasilkan oleh
kekebalan tubuh (T aktif dan limfosit B, makrofag dan monosit) dan non-imun sel (fibroblas ,
sel endotel, sel stroma dan sel-sel kanker) [Steiner et al. (2002)]. Pada jaringan prostat normal
dan neoplastik, IL-6, disekresikan oleh sel epitel basal, merupakan faktor pertumbuhan kuat
autokrin [Giri et al. (2001)]. Its proliferatif tindakan, bersama dengan ekspresinya dalam
stroma dan epitel luminal sel BPH [Royuela dkk. (2001)], menunjukkan bahwa mungkin
merupakan pemain utama dalam IL-17-tergantung BPH-terkait proses inflamasi.
Demikian pula terhadap IL-6, IL-8 disekresikan oleh beberapa jenis sel, seperti monosit,
limfosit T diaktifkan, neutrofil, eosinofil, fibroblas, sel sinovial, adipocytes, sel endotel, sel
epitel dan keratinosit [Steiner et al. (2002)]. Its utama peran dalam rekrutmen neutrofil ke
situs inflamasi, dalam aktivasi dan dalam regulasi sifat imunomodulator mereka [Kobayashi
(2008)] disertai dengan aktivitas chemoattractant pada basofil dan sel T dan oleh tindakan
proangiogenetic ampuh [Proost dkk . (1996)]. Dengan demikian, kemokin ini adalah krusial
terlibat dalam penyakit inflamasi banyak, seperti psoriasis [Numerof & Asadullah (2006)],
rheumatoid arthritis [Paradowska dkk. (2007)], paru inflamasi [Pease & Sabroe (2002)]
penyakit usus dan [MacDermott, 2007], aterosklerosis [Braunersreuther dkk. (2007)] dan
gastritis [Naito dkk. (2005)]. Dalam prostat manusia, IL-8 diproduksi in vitro dan in vivo
dengan beberapa baris sel normal dan kanker dan lima kali lipat up-diatur dalam limfosit
darah perifer dari pasien dengan karsinoma prostat [Waugh & Wilson (2008)]. Selain itu, IL-8
sangat disajikan dalam BPH spesimen [Konig dkk. (2004)] dan tampaknya aktif terlibat
dalam patogenesis BPH. Memang, IL-8 merangsang pertumbuhan berlebih stroma dan epitel,
dengan langsung mempromosikan proliferasi sel epitel pikun [Castro et al., (2004)] dan
akuisisi stroma dari fenotipe myofibroblast reaktif [Schauer dkk. (2008)] dan dengan secara
tidak langsung merangsang sekresi FGF-2 [Giri & Ittmann (2001)]. Pentingnya dalam
peradangan kronis prostat ditandai dengan IL-8 meningkat kadar plasma mani dalam
prostatitis kronis / menahun sindrom nyeri panggul (CP / CPP) dan pada pasien BPH dan
dengan korelasi positif dengan skor gejala dan antigen spesifik serum prostat (PSA) ,
mengidentifikasi IL-8 sebagai penanda pengganti yang dapat diandalkan penyakit peradangan
prostat [Penna dkk. (2007)].
Seperti yang telah kita baru ini menunjukkan [Penna dkk. (2009b)], IL-8 ekspresi dalam
jaringan BPH dapat dianggap berasal tidak hanya untuk epitel tetapi juga untuk sel-sel
stroma, dengan peran fungsional dalam merekrut leukosit mengekspresikan CXCR1 dan
CXCR2 reseptor IL-8. Stimulasi sel stroma BPH dengan Th1 dan Th17 yang diturunkan
sitokin menginduksi sekresi, IL-8 IL-6 dan CXCL-10, sebuah merekrut kemokin ke situs
inflamasi sel kekebalan beberapa, khususnya Th1 lymphocytes. IL-8 langsung
mempromosikan BPH proliferasi sel stroma secara autokrin / parakrin [Penna dkk. (2007,
2009a)], dengan efek maksimal sebanding dengan T dan IGF-1 Des analog (1-3) IGF-1
[Penna dkk. (2009a)]. Oleh karena itu, IL-8 dapat mewakili hubungan antara stroma akibat
respon imun, perawatan peradangan kronis dan pertumbuhan berlebih dari jaringan BPH
(Gambar 1).
Gambar 1. IL-8 secara aktif terlibat dalam benign prostatic hyperplasia (BPH)-terkait
peradangan kronis dan menengahi epitel dan proliferasi sel stroma. Dalam jaringan BPH, sel
epitel dan stroma aktif mengeluarkan IL-8 kemokin proinflamasi dalam menanggapi
rangsangan yang berbeda, termasuk sitokin proinflamasi IFN dan IL-17 yang diproduksi
oleh prostat-infiltrasi sel Th1 dan Th17 masing-masing. IL-8 direkrut ke sel-sel prostat
lymphomononuclear mengekspresikan reseptor serumpun CXCR1 dan CXCR2,
mempromosikan baik secara langsung (melalui tindakan autokrin / parakrin) dan tidak
langsung (melalui induksi faktor pertumbuhan fibroblast (FGFs) -2) proliferasi sel prostat.
Oleh karena itu, IL-8 muncul untuk mewakili rantai kunci antara peradangan kronis dan
pertumbuhan berlebih dari jaringan BPH.
Etiologi peradangan BPH
Acara utama dalam pengaktifan jaringan inflamasi yang menyebabkan remodeling jaringan
BPH masih belum jelas, tetapi hipotesis infektif adalah satu yang masuk akal. Beberapa studi
telah menunjukkan adanya satu set heterogen strain bakteri dan virus dalam sampel BPH
[Sciarra dkk. (2007)]. Selain itu, agonis TLR telah ditemukan untuk menginduksi produksi
sitokin proinflamasi dan kemokin oleh sel stroma BPH, dapat merekrut sel infiltrasi dan
untuk mempromosikan pertumbuhan sel prostat [Penna dkk. (2009b)].
Respon imun BPH-terkait mungkin juga dipicu oleh self-antigen. Zisman dkk. (1995)
membuktikan adanya hubungan langsung antara respon imun dan patogenesis BPH dengan
mendeteksi anti-PSA antibodi dalam serum dari penderita BPH, menyimpulkan bahwa BPH
dapat dipertimbangkan kondisi organ terbatas autoimun yang ditandai dengan tidak adanya
poliklonal B-sel aktivasi. Hipotesis ini kemudian didukung oleh prevalensi subset Th1 dan
Th17, khas penyakit autoimun [Harrington dkk. (2006)], dalam jaringan BPH. Sebagai CP /
CPP adalah delapan kali lebih sering daripada prostatitis bakteri, respon autoimun dapat
merupakan penyebab utama penyakit peradangan prostat [Krieger dkk. (2008)].
Disfungsi neurologis, hormonal dan / atau imunologi telah diusulkan untuk mempengaruhi
CP / CPP patogenesis [Pontari & Ruggieri (2008)]. Sejauh ini, infeksi berkelanjutan dari
setiap organisme menular seksual telah gagal diidentifikasi pada pasien [Weidner dkk.
(1991)], tetapi disregulasi sitokin proinflamasi dan antiinflamasi telah diduga untuk
mempertahankan peradangan dari tumbuhan prostat normal bakteri [lihat Pontari & Ruggieri
(2008) untuk diperiksa]. Selain itu, sebuah serat kepadatan saraf meningkat, kalsitonin
neuropeptida sensorik gen yang berhubungan dengan peptida dan degranulasi sel mast
progresif dengan rilis besar faktor pertumbuhan saraf ketat berkorelasi dengan nyeri pada
CP / CPP dan dapat terlibat dalam peradangan neurogenik dan sensitisasi sentral [lihat Pontari
& Ruggieri (2008) untuk diperiksa].
Di antara hormon seks, penurunan terkait usia testosteron untuk rasio estrogen telah diakui
sebagai faktor penting dalam pengembangan prostatitis kronis. Bahkan, jangka pendek
pemberian estrogen pada tingkat kehamilan ditunjukkan untuk merangsang respon inflamasi
khusus untuk prostat lateral tikus jantan dikebiri, histologi mirip dengan prostatitis nonbakteri spontan [Robinette (1988)] dan terkait dengan peningkatan transkrip kadar IL-1, IL6 dan makrofag inflamasi protein-2 [Harris et al. (2000)]. Sebaliknya, co-pemberian
testosteron dengan prostatitis estradiol mencegah estrogen-induced, sementara DHT kurang
efektif [Naslund dkk. (1986)]. Temuan ini, bersama dengan efek yang menguntungkan
mungkin terlihat dengan tipe 5-reduktase inhibitor II finasteride untuk CP / CPP Nikel [et al.
(2004)], menunjukkan peran pelindung testosteron terhadap peradangan independen dari
konversi kepada DHT. Jika tidak, estrogen telah terbukti mengerahkan peran penting dalam
pengendalian sistem kekebalan tubuh [lihat Straub (2007) untuk diperiksa]. Telah diusulkan
bahwa menghilangnya usia tergantung bertahap androgen dan peningkatan simultan dalam
estrogen menyebabkan melemahnya sistem kekebalan tubuh, dengan mengurangi aktivitas
suatu populasi sel penekan yang secara aktif mendorong dan memelihara toleransi terhadap
antigen prostat [Kramer dkk (2007);. Nikel (2008)]. Saat ini, adalah mapan bahwa proliferasi
tidak terkendali dari sel-sel prostat yang disebabkan oleh peradangan kronis berhubungan erat
dengan inisiasi dan perkembangan neoplastik. Bahkan, infiltrat inflamasi dan atrofi inflamasi
proliferasi (PIA) biasanya digambarkan berdekatan dengan grade tinggi prostatic
intraepithelial neoplasia (PIN) atau kanker dini, sebagai hasil dari proses hyperproliferative
regeneratif konsekuen untuk cedera sel [De Marzo dkk. (2007)]. Sebagai aktivasi isoform
dari reseptor estrogen (ER) telah dihipotesiskan untuk mempromosikan prostat
karsinogenesis, metastasis dan mungkin kemerdekaan androgen [lihat Prins & Korach (2008),
De Marzo dkk. (2007) dan Sciarra dkk. (2008) untuk diperiksa] dan estrogen / androgen
keseimbangan masih merupakan faktor penting dalam pengaturan respon imun dan inflamasi,
estrogen tampaknya menjadi calon yang cocok untuk patogenesis kanker prostat dengan
merangsang ekspresi gen yang terlibat dalam peradangan prostat dan proliferasi [lihat Ho et
al. (2004) untuk diperiksa]. Dalam pandangan ini, peran APC sel stroma prostat serupa
dengan yang diamati pada BPH dapat berkontribusi pada stimulasi hormon peradangan
kronis diusulkan untuk terlibat dalam karsinogenesis prostat melalui produksi estrogeninduced lokal immuno-peraturan faktor. Oleh karena itu, kerusakan jaringan akibat stres
oksidatif, hipoksia, infeksi (kencing dan / atau seksual) atau autoimunitas, bisa memicu
stroma-driven immuno-dimediasi reaksi inflamasi, didukung dan / atau diperkuat oleh
endokrin-imun interaksi dan mengakibatkan pelepasan sitokin progrowth meningkat, generasi
reaktif spesies oksigen-akibat kerusakan DNA dan neovaskularisasi [Sandhu (2008)].
Refluks intraprostatic urin, mungkin karena tekanan intraprostatic meningkat sekunder
terhadap kontraksi sering atau lama uretra dan kandung kemih otot leher yang halus dan
stroma prostat, juga dapat menyebabkan CP / CPP [et al Takechi, 1999.)]. Memang, CP / CPP
gejala terkait telah dibuktikan berkorelasi dengan konsentrasi urat atau kreatinin dalam
sekresi prostat mengungkapkan [Persson & Ronquist (1996)], yang dapat menghasilkan
cedera kimia atau osmolar ke jaringan prostat memulai immuno- dimediasi inflamasi reaksi.
Akhirnya, isolasi CD4 autoreaktif + dan CD8 + limfosit T spesifik untuk antigen prostat dari
individu normal [Corman dkk. (1998)], kapasitas mani plasma [Alexander et al. (1997);
Batstone dkk. (2002)] dan antigen prostat spesifik [Ponniah dkk. (2000); Motrich dkk.
(2005)] untuk menginduksi proliferasi sel mononuklear darah perifer (PBMC) dan CD4 + sel
T, dan self-reaktif CD4 + sel-dimediasi aktivasi sel plasma (dengan produksi tinggi titer
autoantibodi terhadap protein prostat) [Dunphy dkk. (2004)] mendukung respon autoimun
terhadap antigen prostat. Peran dominan dari autoimunitas di CP / CPP pembangunan telah
dikonfirmasi lebih lanjut oleh model murine beberapa yang berkaitan dengan usia spontan
dan antigen-induced prostatitis autoimun eksperimental (EAP) [Vykhovanets dkk. (2007)].
Ini temuan eksperimental, bersama dengan induksi respon sel T oleh sel patogen BPH [Penna
dkk. (2009b)], menyarankan mekanisme umum mempromosikan dan mempertahankan BPH

dan CP / CPP dan, dalam pandangan kami, mendukung teori yang muncul bahwa BPH dapat
dianggap sebagai prostatitis inflamasi asimtomatik. Namun, kurangnya atau korelasi yang
lemah antara peradangan dan infeksi dengan keparahan gejala menunjukkan bahwa faktor
lain selain peradangan dan infeksi berkontribusi pada gejala yang berhubungan dengan CP /
CPP [Nikel (2008)].
Kesimpulannya, prostatitis kronis bakteri dan non infeksi, yang tidak seperti BPH
mempengaruhi laki-laki dari segala usia [Krieger dkk. (2008)], dapat dianggap sebagai latar
belakang patogenetik dari jalur seluler hyperproliferative, mungkin sebagai akibat dari respon
autoimun terhadap antigen diri dirilis menyusul cedera jaringan [Kramer & Marberger
(2006)]. Di antara self-antigen calon, PSA baru-baru ini menunjukkan untuk dapat
mengaktifkan sel T CD4 + dari pasien dengan prostatitis granulomatosa, melalui pengakuan
dari dua antigen HLA-DRB berbeda * 1501-terbatas peptida [Alexander et al. (2004);
Klyushnenkova dkk. (2005)]. PSA antigenisitas mungkin berhubungan dengan selesainya
pengembangan prostat hanya pada pubertas, atau penurunan nilai toleransi proses seluler oleh
usia atau oleh perubahan hormon pada pria penuaan [Kramer & Marberger (2006)]. Hipotesis
bahwa sistem prostat mampu menginduksi dan mempertahankan reaksi autoimun
intraglandular didukung oleh pengamatan in vitro yang CD4 alloreactive + sel T diaktifkan
oleh sel BPH stroma nyata up-mengatur sekresi IL-12 dan IL-23 oleh sel BPH kami, yang
bisa memicu dan memperkuat diferensiasi patogenetik Th1 dan sel Th17 [Penna dkk.
(2009b)] (Gbr. 2).
Gambar 2. Benign prostatic hyperplasia (BPH) sel stroma adalah induser dan target
peradangan kronis prostat. BPH stroma sel mengekspresikan reseptor Pulsa seperti (TLRs),
yang mengenali komponen struktur yang sangat diawetkan antara patogen dan kelas II
kompleks histokompatibilitas utama (MHC) molekul. TLRs aktivasi oleh stimulus infeksi
(bakteri, virus atau jamur) mengarah ke produksi oleh sel stroma BPH sitokin pro-inflamasi
(IL-6) dan kemokin (CXCL10 dan IL-8) dapat merekrut sel infiltrasi dan untuk
mempromosikan pertumbuhan sel prostat pada secara autokrin / parakrin. BPH stroma sel
juga dapat berfungsi sebagai non-profesional antigen sel presentasi (APC) yang mengarah
pada aktivasi infiltrasi CD4 + T limfosit dan mempromosikan diferensiasi mereka di Th1 dan
sel efektor Th17 oleh sekresi IL-12 dan IL-23 masing-masing. Pada gilirannya, aktif dan
limfosit Th1 Th17 menghasilkan sitokin pro inflamasi, seperti IFN dan IL-17,
mempertahankan dan memperkuat kekebalan-mediated respon inflamasi.
VDR agonis dalam pengobatan BPH
Vitamin D produksi dan metabolisme
Vitamin D metabolit yang larut dalam lemak hormon secosteroid disintesis untuk sebagian
besar (90%) oleh aksi sekuensial dari radiasi ultraviolet matahari pada kulit prekursor 7dehydrocholesterol, yang menghasilkan ke cholecalciferol (vitamin D3) pembentukan, dan
kegiatan gabungan enzimatik hydroxylative hati dan ginjal untuk memproduksi pokok
beredar metabolit 25 (OH) D3 dan bentuk aktif 1,25 (OH) 2D3, atau calcitriol masingmasing. 10% sisanya dari turunan vitamin D3 yang dihasilkan dari diet cholecalciferol dan
ergocalciferol (vitamin D2) [Anderson et al. (2004)]. Efek biologis dari calcitriol dimediasi
oleh afinitas tinggi mengikat ke VDR, anggota superfamili reseptor faktor transkripsi nuklir.
Ligan yang tergantung Its perubahan konformasi mempromosikan heterodimerization dengan
reseptor X retinoid (RXR) pada vitamin D-elemen responsif (VDREs) dari gen target, dan
perekrutan reseptor corepressor dan protein coactivator. Kompleks transkripsi menginduksi
intrinsik histone-memodifikasi kegiatan dan rekrutmen langsung dari komponen inisiasi
transkripsi kunci pada promotor yang diatur. Ini hasil interaksi molekul dalam kromatin
renovasi, RNA polimerase II yang dimediasi transkripsi tingkat regulasi dan modulasi
ekspresi gen target [Jones et al. (1998); Carlberg & Polly (1998)]. Sebuah aktivitas terkenal
biologis dari sistem vitamin D adalah pengaturan metabolisme kalsium dan fosfor [DeLuca
(2004)]. Baru-baru ini, agonis VDR telah ditemukan memiliki anti-angiogenetic efek, antiproliferasi dan pro-membedakan tindakan [Napgal dkk. (2005)], serta sifat anti-inflamasi dan
immunoregulatory [Adorini & Penna (2008)].
Vitamin D dan analog dalam penyakit prostat
Sebuah link antara sistem vitamin D dan prostat pertama kali didirikan oleh korelasi
epidemiologi kanker prostat peningkatan insiden dan angka kematian dengan kekurangan
vitamin D [Schwartz (2005)]. Prostat itu kemudian diakui sebagai situs extrarenal sintesis
vitamin D dan tindakan melalui ekspresi 1-hidroksilase dan VDR masing-masing [Ali &
Vaidya (2007)]. VDR ekspresi dalam jaringan berasal dari sinus urogenital, seperti prostat
dan kandung kemih, secara kuantitatif mirip dengan organ target klasik untuk calcitriol,
seperti hati, ginjal tulang, dan, meskipun lebih rendah daripada di usus dan prostat ganas atau
baris sel kandung kemih [Maggi et al. (2006)]. Selain itu, peran pertumbuhan-mengatur
calcitriol disintesis oleh prostat disarankan oleh demonstrasi in vitro dan in sifat antiproliferasi, prodifferentiative, proapoptotic dan anti-invasif vivo pada beberapa model kanker
prostat [Ali & Vaidya (2007)] , dan dengan penurunan tajam dari 1-hidroksilase aktivitas
dalam sel prostat baris kanker [Maggi dkk. (2006)].
Berdasarkan hasil praklinis, efektivitas chemotherapic dari calcitriol, sendiri atau dalam
hubungan dengan klasik anti-tumoral obat (deksametason, docetaxel, carboplatin dan
estramustine), diuji dalam uji klinis beberapa pasien kanker prostat [Harzstark & Ryan
(2008)] . Keterbatasan utama untuk penggunaan klinis dari calcitriol diwakili oleh efek
samping yang hypercalcaemic, yang beberapa protokol terapi berusaha diatasi dengan
pemberian obat intermiten [Beer et al. (2005); Trump dkk. (2006); Beer et al. (2008)].
Sintesis kimia vitamin non-hypercalcaemic analog D, ditandai dengan jendela terapi yang
lebih tinggi dari calcitriol [Napgal dkk. (2005)], telah menyebabkan sintesis lebih dari 2000
molekul yang berbeda, beberapa dari mereka disetujui untuk pengobatan penyakit tertentu
seperti psoriasis, hiperparatiroidisme sekunder atau osteoporosis [Pinette dkk. (2003)].
Manajemen farmakologi dari BPH adalah aplikasi baru dari analog vitamin D, diminta oleh
deteksi ekspresi VDR di prostat berbudaya dan sel stromal berasal dari kandung kemih
penderita BPH [Maggi dkk. (2006)]. Mengurangi pertumbuhan berlebih prostat dengan
menurunkan intra prostat androgen sinyal, tanpa langsung mengganggu kerja androgen
sistemik, akan meniadakan efek samping sistemik anti-androgen, seperti 5-reduktase
inhibitor. Selain itu, agonis VDR tampilkan ditandai sifat anti-inflamasi dan kelas ini agen
karena itu bisa merupakan suatu pilihan terapi menarik untuk pengobatan farmakologi dari
BPH et [Maggi al. (2006)].
Agonis VDR mengobati BPH terkait LUT
Studi praklinis dilakukan di laboratorium kami telah menunjukkan pertumbuhan berkurang
dan kelangsungan hidup sel BPH utama stroma oleh dua non-hypercalcaemic agonis VDR,
BXL-353 dan BXL-628 (elocalcitol) [Maggi dkk. (2006)]. Secara khusus, elocalcitol, yang
lebih kuat daripada BXL-353, penurunan testosteron akibat proliferasi sel BPH sampai batas
yang sama dari finasteride dan asetat cyproterone, mendorong apoptosis bahkan dalam
kehadiran faktor pertumbuhan intraprostatic dan benar-benar berlawanan efek stimulasi
androgen pada subpicomolar konsentrasi. Namun, aksi anti-androgenik tidak diberikan
melalui campur tangan langsung dengan sinyal AR, sebagai elocalcitol tidak memodifikasi
5-reduktase tipe I dan II kegiatan, dan tidak mengikat AR atau mempengaruhi aktivitas
transkripsi nya [Crescioli dkk. (2004)]. Oleh karena itu, kita hipotesis bahwa mekanisme
molekuler yang terlibat dalam efek anti-proliferasi dan pro-apoptosis agonis VDR dalam sel
BPH bisa beroperasi hilir AR. Bukti yang mendukung hipotesis ini mencakup autofosforilasi
penurunan KGFR dan IGF1R, penangkapan progresi siklus sel pada G1, dengan peningkatan
paralel dalam ekspresi clusterin dan penurunan ekspresi anti-apoptosis faktor bcl-2, yang
secara positif dipengaruhi oleh androgen dan KGF [et Crescioli al. (2004)].
Elocalcitol secara signifikan menurunkan pertumbuhan prostat baik dalam unmanipulated
dan pada tikus T-diganti dikebiri, dengan efek yang sebanding dengan finasteride tapi tanpa
mempengaruhi sekresi testis androgenik atau fungsi hipofisis Crescioli et [al. (2004)].
Menariknya, kedua sel epitel dan stroma prostat dari elocalcitol yang diobati tikus
menunjukkan tingkat apoptosis meningkat dan ekspresi clusterin, membenarkan dalam
pengamatan in vitro [Crescioli dkk. (2004)]. Seperti tikus tidak mengembangkan BPH
spontan, potensi anti-hyperplasic dari elocalcitol diuji pada anjing beagle jantan kronis
dirawat selama 9 bulan dengan 5 mg / kg / mati. Dalam model ini, kami mengamati
penurunan berat prostat, lebih jelas setelah pemulihan 2-bulan, menunjukkan aktivitas
farmakologi berkepanjangan dari senyawa ini, dengan tidak adanya efek samping [Adorini
dkk. (2007)].
Data-data praklinis diminta seminggu 12-fase IIa, multisenter, buta ganda, acak, kontrol
plasebo klinis bertujuan untuk mengevaluasi efikasi dan keamanan elocalcitol administrasi
(150 mg / mati) di BPH pasien [Colli et al. (2006)]. Elocalcitol dipamerkan penurunan 7,2%
dalam volume prostat, diukur dengan MRI panggul, dibandingkan dengan plasebo. Yang
penting, 92% dari elocalcitol pasien yang diobati tidak mengalami pertumbuhan yang
signifikan secara klinis dalam volume prostat dibandingkan dengan 48% pada kelompok
plasebo. Dengan demikian, pengurangan volume prostat pada elocalcitol-diperlakukan
kelompok terhadap peningkatan yang ditandai dalam kelompok plasebo menunjukkan
kemampuan ini agonis VDR untuk memblokir proses BPH yang sedang berlangsung. Selama
persidangan, tidak ada perbedaan diamati pada skor gejala atau parameter Fungsi Ginjal,
mungkin karena durasi singkat studi bukti-konsep dan karena pasien tidak diskrining untuk
gejala tetapi hanya untuk volume prostat [Colli et al. (2006)].
Untuk menjelaskan poin ini, 6-bulan fase IIb penelitian dilakukan untuk mengukur laju aliran
kemih maksimum dan keparahan gejala sekunder sebagai titik akhir pada pasien dengan
setidaknya simtomatologi moderat. Elocalcitol efektif dalam meningkatkan kemih laju alir
maksimum (Qmax) dan ameliorating LUT, serta menahan pertumbuhan prostat dan
mencegah risiko AUR dan perlu untuk operasi [Montorsi & Colli (2008)], semua parameter
kunci dari perkembangan BPH. Mengingat korelasi miskin antara LUT dan ukuran prostat
terutama di fase awal BPH pembangunan, mekanisme yang mendasari perbaikan mereka
dapat disebut efek langsung dari elocalcitol pada otot kandung kemih dan komponen dinamis
dari patogenesis LUT [Crescioli dkk. (2005); Morelli dkk. (2007)].
Obstruksi uretra ditentukan oleh prostat hiperplastik dikompensasi dalam tahap awal oleh
hipertrofi dinding kandung kemih dan aktivitas kontraktil otot meningkat. Kemudian, otot
kandung kemih halus menjadi disfungsional, dengan lebih sering berkemih spontan nonkontraksi dan mengurangi kemampuan untuk menghasilkan tekanan berkemih efisien.
Sebagai obat antikolinergik, pengobatan lini pertama untuk kandung kemih terlalu aktif,
menyebabkan efek samping yang tidak menyenangkan (mulut kering, konstipasi, takikardia
dan gejala sistem saraf pusat) karena tidak lengkap selektivitas mereka [Andersson (2004)],
strategi terapi alternatif yang dicari. Agonis VDR mengurangi pertumbuhan sel kandung
kemih manusia, menginduksi apoptosis dan mengatur renovasi otot fenotip halus, dengan
mengurangi ekspresi penanda myofibroblast diaktifkan seperti desmin dan smoothelin
[Crescioli dkk. (2005)].
Konsisten dengan peran RhoA / ROCK sinyal dalam mengatur kontraksi kandung kemih
manusia dan tikus dan nada, khususnya dalam menghasilkan kontraksi spontan [Peters dkk.
(2006)], kami telah menunjukkan bahwa elocalcitol mempengaruhi kontraktilitas kandung
kemih melalui penghambatan kalsium peka RhoA / ROCK jalur dengan mengganggu RhoA
aktivasi [Morelli dkk. (2007)]. Pengurangan RhoA / ROCK-dimediasi kontraksi kandung

kemih tidak tepat disebabkan oleh elocalcitol tidak mengganggu motilitas detrusor
keseluruhan, mencegah retensi kemih akibat membatalkan penurunan nilai. Sebagai
kesimpulan, hasil kami menunjukkan efek menguntungkan kemungkinan elocalcitol pada
kandung kemih terlalu aktif oleh dua mekanisme: menangkal ekspresi ditingkatkan dan sinyal
faktor pertumbuhan yang terlibat dalam hipertrofi otot polos kandung kemih dan hiperplasia
[Crescioli dkk. (2005)], dan meningkatkan efisiensi kontraktil sel otot kandung kemih
melalui modulasi dari gen otot ekspresi halus dan ke bawah-peraturan sensitisasi
myofilament otot polos untuk kalsium [Morelli dkk. (2007)].
Berdasarkan tempat praklinis, sebuah fase IIa, double blind, placebo-controlled studi telah
menunjukkan kemanjuran sinyal yang jelas pada titik akhir primer (berarti volume voided per
berkemih) dan gejala, termasuk frekuensi, nokturia dan inkontinensia episode [Colli et al .
(2007)]. Sebuah multi-pusat percobaan fase IIb sedang berlangsung.
Imunomodulator sifat agonis VDR
Imunomodulator sifat agonis VDR diselidiki setelah ditemukannya ekspresi VDR dalam tipe
sel sebagian besar sistem kekebalan tubuh, khususnya di APC (makrofag dan sel dendritik)
dan limfosit T [Adorini & Penna (2008)]. Sel target utama adalah agonis VDR APC dan
limfosit T, yang aktivitasnya dipengaruhi baik secara langsung maupun tidak langsung,
melalui modulasi aktivasi APC. Beberapa sitokin kunci dalam limfosit T telah terbukti
menjadi sasaran ligan VDR, khususnya Th1 tipe sitokin, yang secara langsung menghambat
sekresi dengan penghambatan selektif yang dihasilkan dari sel T efektor pathogentic
pengembangan [Adorini & Penna (2008)]. Calcitriol juga telah terbukti, di bawah kondisi
yang sesuai, untuk meningkatkan perkembangan sel-sel Th2 melalui efek langsung pada CD4
+ sel naif dan peningkatan IL-4 transkripsi. Efek menguntungkan dari agonis VDR telah
dibuktikan dalam pencegahan dan pengobatan beberapa penyakit autoimun eksperimental,
termasuk lupus erythematosus, encephalomyelitis alergi eksperimental, kolagen akibat
artritis, Lyme arthritis, penyakit radang usus dan tipe I diabetes, dan juga dalam penolakan
allograft [ Adorini & Penna (2008)].
Sebuah aspek novel agonis VDR dalam pengobatan penyakit autoimun ini disediakan oleh
induksi CD4 + CD25 + Foxp3 + peraturan T sel. Peran penting dalam kegiatan
immunoregulatory agonis VDR dimainkan oleh kemampuan mereka untuk nyata memodulasi
fenotipe dan fungsi APC, khususnya sel dendritik (DC), baik in vitro dan in vivo. Tidak
hanya kalsitriol menghambat produksi IL-12 [D'Ambrosio dkk. (1998)], tetapi vitamin D dan
analog nya menginduksi monosit-dan tulang sumsum yang diturunkan DC untuk memperoleh
sifat tolerogenic oleh down-mengatur ekspresi CD40, CD80 dan CD86, dengan membatalkan
IL-12 sekresi dan dengan sangat meningkatkan IL- 10 produksi [Adorini & Penna (2008)].
Properti ini immunomulatory menyebabkan induksi toleransi transplantasi pada hewan model
penolakan allograft [Gregori dkk. (2001); Griffin et al. (2001)]. Selain itu, APC dapat
mensintesis dan mensekresikan calcitriol karena ekspresi mereka 1-hidroksilase, yang kuat
dirangsang oleh IFN et [Overbergh al. (2000)]. Dengan demikian, APC-berasal calcitriol
fisiologis dapat berkontribusi secara lokal mengatur respons imun bawaan dan adaptif.
Imunomodulator efek agonis VDR di prostatitis inflamasi kronis
Non-obesitas diabetes (NOD) tikus mengembangkan prostatitis autoimun eksperimental
(EAP) setelah imunisasi dengan mouse prostat homogenat diemulsikan dalam adjuvan
Freund lengkap di [Vykhovanets dkk. (2007)]. Administrasi elocalcitol pada dosis
normocalcaemic in EAP yang sudah mapan selama 2 minggu (secara lisan lima dosis /
minggu pada 100 mg / kg dari hari 14 sampai 28 pasca imunisasi) mengurangi 67% jumlah
infiltrat intraprostatic dibandingkan dengan kendaraan tikus yang diobati. Penurunan ditandai
sel inflamasi intraprostatic (CD4 + dan CD8 + sel T, sel B, makrofag dan DC) infiltrasi
ditandai oleh proliferasi berkurang dan kematian aktivasi diinduksi sel yang disempurnakan,
lebih unggul dari yang diinduksi oleh dosis optimal deksametason [Penna efek et al. (2006)].
Efek molekul elocalcitol yang diberikan melalui penghambatan CD4 + respon sel T pada
prostat-infiltrasi sel dan dalam prostat pengeringan sel kelenjar getah bening, seperti yang
ditunjukkan oleh produksi vivo berkurang ex IFN dan IL-17 dan nyata menurun ekspresi
iNOS, kunci enzim yang dibutuhkan untuk sintesis agen inflamasi NO [Tinker & Wallace
(2006)], dan NO itu sendiri, dalam makrofag peritoneal. Tindakan penghambatan elocalcitol
pada respon sel T juga dikonfirmasi pada tikus NOD diimunisasi dengan protein pengikat
prostat steroid (PSBP) atau epitop imunodominan nya PSBP21-40. Selain itu, respon
berkurang menjadi PSBP diamati pada NOD. Parah serta immunodeficiency (SCID)
penerima ditransfer dengan CD4 + sel T dari elocalcitol tikus yang diobati NOD [Penna dkk.
(2006)], sesuai dengan kemampuan agonis VDR untuk menghambat mekanisme patogen
dalam beberapa sel Th1-tergantung penyakit autoimun [Adorini & Penna (2008)]. Elocalcitol
mampu menghambat proliferasi dan menginduksi apoptosis tidak hanya sel T patogen tetapi
juga sel-sel epitel dan stroma prostat, menunjukkan efek ganda dalam mempromosikan
pemeliharaan arsitektur kelenjar normal. Akhirnya, analisis dosis-respons efek elocalcitol
menunjukkan bahwa sekitar 60% pengurangan jumlah infiltrat intraprostatic, dibandingkan
dengan kendaraan yang diobati hewan, sudah diperoleh dengan 3 mg / kg, dosis 30 kali lipat
lebih rendah dari toleransi maksimum dosis senyawa ini dalam hal hypercalcemia. Dengan
demikian, jendela terapeutik elocalcitol dalam pengobatan EAP adalah agak lebar [Penna
dkk. (2006)].
Elocalcitol menghambat IL-8-tergantung BPH stroma proliferasi sel dan respon peradangan
Kami baru menunjukkan bahwa elocalcitol menghambat IL-8 produksi diinduksi oleh sitokin
proinflamasi yang disekresikan oleh prostat-infiltrasi sel T CD4 + (IFN-, IL-17 dan TNF-)
pada manusia sel stroma prostat, disertai dengan berkurangnya COX-2 ekspresi dan
prostaglandin E2 (PGE2) produksi, dan penangkapan para translokasi nuklir nuklir faktor-kB
(NF-kB), suatu faktor transkripsi yang mengatur juga IL-8 produksi. IL-8 mempromosikan
BPH pertumbuhan sel dan elocalcitol dosis ketergantungan melawan IL-8-tergantung BPH
proliferasi sel melalui penghambatan RhoA / ROCK jalur [et al Penna. (2009a)]. Efek ini
konsisten dengan peran ini signaling kalsium sensitisasi dalam pengaturan proses inflamasi
[Segain dkk. (2003); Schmeck dkk. (2003)], melalui aktivasi NF-kB et [Perona al. (1997);
Montaner dkk. (1998)] dan induksi IL-8 sekresi et [Zhao al. (2002, 2003)].
Oleh karena itu, data ini memberikan penjelasan mekanis untuk peran IL-8 dalam patogenesis
BPH, menunjukkan bahwa kombinasi dari Th1 dan Th17 sel yang diturunkan sitokin
inflamasi nyata dapat merangsang sekresi oleh sel stroma BPH. Selain itu, hasil kami
menunjukkan link IL-8-tergantung menjembatani respon inflamasi dan proliferasi sel dalam
patogenesis BPH, yang dapat ditargetkan dengan elocalcitol melalui beragam mekanisme
aksi. Akhirnya, ekspresi VDR peningkatan dipromosikan oleh T sel yang diturunkan sitokin
inflamasi dalam sel BPH membuat mereka lebih rentan terhadap aksi penghambatan
elocalcitol et [Penna al. (2009a)].
Kesimpulan
Peradangan kronis dapat dianggap sebagai komponen ketiga patogenesis BPH, mengambil
bagian dengan sinyal AR dalam induksi jaringan renovasi khas tahap lanjutan dari penyakit.
Sel stroma prostat mengerahkan peran penting dalam induksi respon inflamasi, dengan
mengaktifkan CD4 + limfosit dan mendukung diferensiasi mereka ke subset Th1 dan Th17
efektor [Penna dkk. (2009b)]. Dengan demikian, BPH dapat dilihat sebagai bentuk prostatitis
inflamasi asimtomatik, yang patogenesis mungkin dipicu oleh infeksi. Pelepasan prostat diri
antigen kerusakan jaringan berikut mungkin peka sistem kekebalan tubuh dan mulai respon
autoimun. Di antara sitokin proinflamasi dan kemokin diproduksi oleh lingkungan mikro
prostat, stroma yang diturunkan IL-8 dapat dianggap sebagai mata rantai kunci antara
peradangan kronis dan proliferasi sel stroma. Upregulation VDR dalam sel BPH setelah
terkena rangsangan proinflamasi menguatkan anti-inflamasi dari elocalcitol agonis VDR,

yang mampu menghambat jalur COX-2/PGE2, translokasi nuklir NF-kB dan RhoA / ROCK
sinyal [Penna dkk. (2009a)]. Secara khusus, efek pada jalur ini sensitisasi kalsium mungkin
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Chronic Inflammation in The Pathogenesis of Benign Prostatic Hyperplasia

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Chronic Inflammation in The Pathogenesis of Benign Prostatic Hyperplasia

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Chronic inflammation in the pathogenesis

of benign prostatic hyperplasia

leucocytes organize in nodular infiltrates characterized by specific phenotypic and functional

This complex proinflammatory microenvironment is closely related to BPH stromal

through the maintenance of the inflammatory microenvironment and the amplification of

Aetiology of BPH inflammation

VDR agonists in BPH treatment

suggesting a prolonged pharmacological activity of this compound, in the absence of side

Immunomodulatory effects of VDR agonists in chronic inflammatory

We have recently demonstrated that elocalcitol inhibits IL-8 production induced by

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