Journal of Neuroimmunology 180 (2006) 104 – 116

www.elsevier.com/locate/jneuroim

Point of view
Neural–endocrine–immune complex in the central modulation of
tumorigenesis: Facts, assumptions, and hypotheses
Boris Mravec a,b,⁎, Yori Gidron c , Barbara Kukanova b , Jozef Bizik d ,
Alexander Kiss b , Ivan Hulin a
a
Laboratory of Neurophysiology, Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic
b
Laboratory of Functional Neuromorphology, Institute of Experimental Endocrinology, Slovak Academy of Sciences,
Vlarska 3, 833 06 Bratislava, Slovak Republic
c
University of Tilburg, 5000 LE, Tilburg, The Netherlands
d
Cancer Research Institute, Slovak Academy of Sciences, Vlarska 6, 833 06 Bratislava, Slovak Republic
Received 22 June 2006; received in revised form 7 July 2006; accepted 7 July 2006

Abstract

For the precise coordination of systemic functions, the nervous system uses a variety of peripherally and centrally localized receptors,
which transmit information from internal and external environments to the central nervous system. Tight interconnections between the
immune, nervous, and endocrine systems provide a base for monitoring and consequent modulation of immune system functions by the brain
and vice versa. The immune system plays an important role in tumorigenesis. On the basis of rich interconnections between the immune,
nervous and endocrine systems, the possibility that the brain may be informed about tumorigenesis is discussed in this review article.
Moreover, the eventual modulation of tumorigenesis by central nervous system is also considered. Prospective consequences of the
interactions between tumor and brain for diagnosis and therapy of cancer are emphasized.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Autonomic nervous system; Brain; Cytokines; Tumorigenesis; Vagus nerve

1. Introduction A plethora of evidence, accumulated mainly during the

The central nervous system (CNS) provides a precise
coordination of all body functions utilizing the signals from
internal environments (Ádám, 1998). To aid such coordination
in organisms, highly differentiated systems of visceral receptors
have been developed. Visceral receptors are able to monitor a
wide range of biological parameters (e.g. concentration of
chemical compounds in plasma, osmotic pressure, mechanical
pressure, etc.). Therefore, visceral receptors are important
components of internal conveying systems that participate in
the maintenance of homeostasis (Berthoud, 2004).
⁎ Corresponding author. Institute of Pathophysiology, Faculty of Medicine,
Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic.
Tel.: +421 2 59357613; fax: +421 2 59357601.
E-mail address: ueenmrav@savba.sk (B. Mravec).
0165-5728/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jneuroim.2006.07.003
first half of the 20th century, indicates that the endocrine and
nervous systems integrate and regulate different body
functions. In addition, many studies demonstrate that
immune mechanisms may also be influenced by these sys-
tems (Besedovsky and del Rey, 1996). Lastly, rich inter-
connections take place between neural, endocrine, and
immune systems (Andersson, 2005; Blalock, 2002; Downing
and Miyan, 2000),which may constitute a neural–endocrine–
immune functional complex (Kvetnoy, 2002). The hypothal-
amus with its paraventricular nucleus represents an important
anatomical link in this complex, which integrates the acti-
vities of all three systems (Turnbull and Rivier, 1999).
The nervous and immune systems can bi-directionally
communicate by using a common chemical language
employing neurotransmitters, neurohormones, hormones,
cytokines and the common respective receptors (Savino and
 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116 105

Dardenne, 1995; Blalock, 2005). The immune system may
work as a complex of sensors informing the nervous system
about changes in the immune function of organism and
about internal threats (Blalock, 1984). The genesis and
progression of tumors are intimately interconnected with the
immune system. The cells and molecules of the immune
system are highly involved in tumorigenesis, on one hand
playing an important role in eliminating and annihilating a
wide scale of pathogens and transformed cells (Chaplin,
2003; Delves and Roitt, 2000a,b; Parkin and Cohen, 2001)
and on the other hand in some cases facilitating tumorigen-
esis at various stages (Pikarsky et al., 2004; Balkwill and
Mantovani, 2001). Tumorigenesis evokes both humoral and
cellular responses of the immune system (Chiplunkar,
2001).
In this review, an attempt was done to extend and sum-
marize the recent data supporting the hypothesis that the
central nervous system can monitor and modulate tumori-
genesis, beyond the role of the vagus nerve alone (Gidron et
al., 2005). This assumption was based on a complex of
anatomical and functional interrelationships between ner-
vous, endocrine and immune systems, which in the future
might open new avenues in cancer research with a possible
impact on prevention, diagnosis and therapy of cancer.

Fig. 1. Pathways, which transmit information from the immune system to the brain (A–D). (A) Cytokines (e.g. IL-1,a IL-6, TNF) circulating in blood stream
influence brain activity via circumventricular organs (e.g. subfornical organ—SFO, organum vascullosum lamine terminalis—OVLT, area postrema—AP) or
via interaction with brain endothelial cells. (B) Binding of cytokines (e.g. IL-1) to receptors on vagal paraganglion dendritic cells (grayish cell with protrusions)
or directly to receptors of the vagus nerve activate vagus nerve afferents that transmit information to the NTS. (C) Endorphins (β-END) might bind to the
endings of somatic afferents and produce an analgesic effect. (D) Whether sympathetic nerve afferents are influenced by some compound (?) released from
immune cells remains to be investigated. Because the vagus nerve innervates only limited visceral areas, it is possible that information is carried via the
sympathetic afferents.
106 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
2. Messages conveying pathways from the immune
system to the brain
The CNS can monitor activities of the immune system
mainly via two pathways: humoral and neural (Fig. 1;
Dantzer et al., 2000; Elmquist et al., 1997; Goehler et al.,
2000; Pavlov et al., 2003). While the humoral pathways are
relatively slow and less informative regarding the location or
source of the immune signals, the neural pathways, on the
contrary, are fast and location specific.
2.1. Humoral pathways
Cytokines are key messengers involved in the transmis-
sion of signals from the immune to the nervous system
(Mantovani, 1999; Sternberg, 1997). They can exert their
effect on the nervous system utilizing different routes. Recep-
tors for cytokines are present in many peripheral structures as
well as in the CNS (Rothwell and Hopkins, 1995). Inter-
actions with autonomic nerves (especially the vagus nerve)
and with peripheral somatic nerves are discussed bellow.
Another route for signal transmissions is represented by an
indirect interaction of circulating cytokines with the brain
(Licinio and Wong, 1997). The brain is informed about
cytokines that circulate in the blood and reach the brain
circulation at least by three different pathways that may
convey information from the immune system to the CNS: a)
cytokines can pass the blood–brain barrier (BBB) at the level
of circumventricular organs (CVOs) and bind to receptors on
macrophages (Buller, 2001); b) circulating cytokines may
activate the cerebral endothelial cells, which in turn transmit
signals to perivascular macrophages that activate the mi-
croglia within the brain parenchyma (Elmquist et al., 1997;
Perry, 2004); and c) cytokines may be actively transported by
the endothelium across the BBB (Quan and Herkenham,
2002; Turrin and Rivest, 2004). It is important to note that
cytokines binding to receptors on macrophages, endothelial
cells, or astrocytes induce the production of soluble mole-
cules (e.g. prostaglandins, nitric oxide) that convey the signal
from the circulation to the CNS (Konsman et al., 2002;
Nadeau and Rivest, 1999; Szelenyi, 2001; Turrin and Rivest,
2004; Watkins et al., 1995). It has been suggested that
prostaglandins may also be crucial messengers that constitute
links between circulatory cytokines and the CNS (Quan and
Herkenham, 2002; Rivest, 2001; Turnbull and Rivier, 1999).
In addition, the presence of receptors for cytokines in the non-
tanycytic portions of the ependymal lining, the choroid ple-
xus and vascular endothelium, suggests that the endothelial
cells might participate in the transmission of immune signals
to the CNS (Ericsson et al., 1995; Harre et al., 2002; Turrin
and Rivest, 2004; Vallieres and Rivest, 1997). Circulating IL-
1α has direct access to cortical brain cells located behind the
BBB through a saturable transport system that provides a
pathway by which the brain and immune systems interact
(Banks et al., 1993). Thus, activation of endothelial cells in
the BBB followed by secretion of specific messenger mole-
cules such as prostaglandins, seem crucial for humoral im-
mune-to-brain communication.
Circumventricular organs play a critical role as transdu-
cers of information between the blood, neurons, and cerebral
spinal fluid. They permit both the release and sensing of
chemical compounds without disrupting the BBB. Therefore
they play an essential role in the regulation of diverse physio-
logical functions (e.g. control of the cardiovascular function,
body fluid regulation, feeding behavior, and reproduction).
Moreover, CVOs are significantly involved in the central
immune responses (Buller, 2001; Cottrell and Ferguson,
2004; Ferguson and Bains, 1996; Ganong, 2000). There are
two main arguments that support the emergence of CVOs as
important CNS structures in the immune regulations: a) all
sensory CVOs (the subfornical organ, the organum vasculo-
sum of the lamina terminals and the area postrema) possess
receptors for cytokines, i.e. IL-1β, IL-6; TNF that provide a
basis for transmission of immune signals to the brain
(Ericsson et al., 1995; Nadeau and Rivest, 1999; Roth et
al., 2004; Turrin and Rivest, 2004) and b) cells of the CVOs
show physiologically relevant morphological and electro-
physiological changes during the early phase of the immune
response (Cottrell and Ferguson, 2004). Thus, the humoral
pathways may convey immune information in certain
physiological contexts.
2.2. Neuronal pathways
Information from the immune system may also reach the
CNS via peripheral nerves. Cytokines play a pivotal role in
the transmission of signals from the immune system to
peripheral nerves. However, other peptides/proteins are also
involved in the interaction between the immune and peri-
pheral nervous system. Immune cells are capable of synthe-
sizing many peptide hormones and neurotransmitters, e.g.
corticotrophin releasing hormone (CRH), adrenocorticotro-
pic hormone (ACTH), endorphins, thyroid stimulating hor-
mone, growth hormone, prolactin, substance P, vasopressin,
oxytocin, somatostatin, and neuropeptide Y (Savino and
Dardenne, 1995; Petrovsky, 2001; Shepherd et al., 2005).
These compounds do not act only in a paracrine manner. For
example, immune cell-derived β-endorphins might act on
opioid receptors on the peripheral terminals of sensory
neurons (Blalock, 1994).
Peripheral nerves could receive information directly from
specialized immune cells or from sentinel cells, e.g. dendritic
cells and subpopulations of tissue fibroblasts. Sentinel cells
process information about the immune status of surrounding
tissue and may consequently transmit these signals to the
peripheral nervous system via production of cytokines
(Buckley et al., 2001; Kaufman et al., 2001; Smith et al.,
1997). It is suggested that sentinel cells might represent an
analogy to taste cells. Both, the sentinel and taste cells are in
the first line of contact with the chemical stimulus, and res-
pond by generating a second signal capable of activating
neural elements (Goehler et al., 2000).
 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
One of the most important visceral sensors is represented
by the vagus nerve. It innervates the thorax and abdomen with
fibers containing a variety of sensory receptors (Paintal,
1973). The role of the vagus nerve in the transmission of
information about peripheral inflammatory processes is well
recognized. The data indicate that capsaicin-sensitive afferent
fibers of the hepatic vagus nerve constitute necessary com-
ponents of the afferent mechanism of the first febrile phase
(Romanovsky et al., 2000). This is supported by data
showing that vagal sensory neurons themselves express
mRNA for IL-1 receptors, suggesting a direct reaction of
afferent vagal fibers to IL-1 (Ek et al., 1998). Therefore,
cytokines might activate the sensory afferents of the vagus
nerve, which transmit signals from the immune system to the
CNS, particularly to the nucleus of the solitary tract (Maier et
al., 1998; Perry, 2004). While the role of the vagus in
immune-to-brain communication is quite established (Ek et
al., 1998; Goehler et al., 1998), this may be limited to low
concentrations of peripheral pro-inflammatory cytokines
(Hansen et al., 2000). This role may be pertinent to low
concentrations of inflammation that can promote tumorigen-
esis, as described below. Another group of important visceral
sensors are paraganglia, which represent structures support-
ing transmission of information from the immune system to
the brain via the vagus nerve (Watkins et al., 1995). Para-
ganglia, innervated by the vagus nerve, contain cells that
express IL-1 receptors. This arrangement represents an
important link between the immune and nervous systems
(Goehler et al., 1997, 1999). IL-1 receptors appear to be
located on dendritic-like cells as well, interdigitating the
vagus nerve parenchyma (Licinio and Wong, 1997). In the
paraganglia, immune cells are activated during inflammation
and consequently may stimulate the vagus nerve endings.
Therefore, immune cells of paraganglia are responsible for
the indirect activation of the vagus nerve (Goehler et al.,
2000). Interestingly, some data suggest, that the carotid body
(paraganglion involved in the monitoring of blood oxygen-
ation), also expresses cytokine receptors for the monitoring of
immune signals (Wang et al., 2002a). The vagus nerve does
not innervate all visceral organs. Therefore it can be hy-
pothesized that sympathetic sensory (afferent) fibers might
also transmit certain immune-related information from the
vagus innervation-free visceral regions of the body. While the
vagus nerve mediation of immune signals from the visceral
regions is well characterized, the role of the cutaneous
sensory nerves in transmission of immune signals is less
clear. However, experiments using bacterial lipopolysaccha-
ride-induced inflammation and local anesthesia indicate that
cutaneous sensory nerves can modestly participate in the
transmission of inflammatory information to the CNS (Roth
and De Souza, 2001). Tactile hypersensitivity during
inflammatory diseases and observations in patients with
leprosies also suggest a possible role of cutaneous sensory
afferent fibers in transmission of signals from the immune
system to the CNS (Hermann et al., 2005). It is presumed, that
disruption of sensory C-fibers and sympathetic innervation in
107
leprosies is responsible for the loss of anti-inflammatory
immune–nervous system communicative and modulatory
circuits (Rook et al., 2002).
3. Messages conveying pathways from the brain to the
immune system
The CNS has the capacity to deliver neurotransmitters and
neuropeptides to all tissues in the body. For a long time, the
immune system was considered an exception to this rule.
However, it is now clear that the thymus, spleen, and other
lymphoid organs are also innervated by the nervous system.
Therefore the nervous system, including the brain and the
peripheral nervous system, can stimulate or inhibit activities of
the innate and adaptive immune systems via two ways, neural
and humoral (Fig. 2; Berczi, 2001; Brogden et al., 2005).
3.1. Humoral pathways
The main messengers of humoral communication between
the brain and the immune system are hormones released from
adenohypophysis (Berczi, 2001). It was shown that after
parturition, the function of the bone marrow, the thymus and
the maintenance of immunocompetence, all became depen-
dent on the pituitary prolactin (PRL) and growth hormone
(GH). Thyroid stimulating hormone modulates immune
functions both by the stimulation of thyroid hormones and
by its action on the lymphoid cells (Berczi, 1997, 1994;
Fabris et al., 1995).
The proopiomelanocortin derived peptides – ACTH,
α-melanocyte stimulating hormone (α-MSH) and β-endor-
phin (β-END) – act antagonistically to GH and PRL and
suppress adaptive immune responses by acting on the nervous,
endocrine and immune systems (Berczi, 2001; Vamvakopou-
los and Chrousos, 1994). It has been shown that α-MSH
suppresses nuclear factor-κB (NF-κB) activated by various
inflammatory agents and that this mechanism probably
contributes to α-MSH induced anti-inflammatory effects
(Manna and Aggarwal, 1998). The influence of ACTH on
immune status is mediated mainly via glucocorticoids, re-
leased from the adrenal gland, which affect immune responses
via glucocorticoid receptors expressed by immune cells.
Whereas it was initially thought that glucocorticoids mediate
immunosuppression, more recent studies indicate that they
suppress Th1 and activate Th2 cytokines (Almawi et al.,
1999). Thus, ACTH-induced changes of immune system
activity are not always immunosuppressive, but rather immu-
nomodulatory (Sternberg, 1997). It is necessary to take into
consideration that immune cells also possess a capacity to
produce some hormones, e.g. PRL, GH (Savino and
Dardenne, 1995). Another humoral “effector” of immunity is
oxytocin, a hormone synthesized in the hypothalamus and
secreted from the pituitary gland. Oxytocin has immunomod-
ulatory roles (e.g., Yang et al., 1997) and is relevant to
tumorigenesis since it may have a role in suppressing tumor
cell proliferation (Cassoni et al., 2004).
108 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116

Therefore, the interplay between hormones released from
the CNS and immune cells might participate in the modu-
lation of immune functions.
3.2. Neuronal pathways
Both the sympathetic and parasympathetic parts of the
autonomic nervous system may modulate immune processes
in the organism. All lymphoid organs receive autonomic
innervation and cells located in the lymphoid tissues possess
receptors for transmitters released from autonomic nerves
(Czura and Tracey, 2005; Dardenne and Savino, 1994;
Elenkov et al., 2000).
The immune system is regulated, to a great extent, by the
sympathetic nervous system (SNS), which innervates the
majority of lymphoid organs (Basu and Dasgupta, 2000;
Weigent and Blalock, 1987; Denes et al., 2005). For example,
the spleen has exclusively only sympathetic innervation
(Stevens-Felten and Bellinger, 1997). It is well documented
that catecholamines released from sympathetic nerve endings
modulate the function of many components of the immune
system via adrenergic and purinergic receptors on immune
cells (Elenkov et al., 1995, 2000; Hasko and Szabo, 1998;
Tracey, 2002; Vizi et al., 1995). Recent findings also show
that the SNS is important in the regulation of the egress of
hematopoietic cells from bone marrow (Katayama et al.,

Fig. 2. Pathways, which transmit information from the brain to the immune system (A–E). (A) Hormones released from the pituitary gland (e.g. ACTH, prolactin,
GH) might modulate immune function. (B) Acetylcholine released from postsganglionic vagal neurons (VNpo) bind to nicotine receptors of immune cells and
produces an anti-inflammatory effect. (C, D) Norepinephrine released from postganglionic sympathetic neurons (SNpo) and epinephrine/norepinephrine released
from adrenal medulla might influence immune functions after binding to adrenergic receptors on the immune cells. (E) Glucocorticoids released from adrenal
cortex have complex effects on the immune system. The schema omits modulation of immune cells by somatic afferent sensory fibers that activated by
inflammatory processes release neuropeptides via axonal reflex manner. Similarly, release of norepinephrine from sympathetic nerve ending might be modulated
by cytokines released from neighboring immune cells (Straub et al., 1998). However, these mechanisms are primarily a consequence of local peripheral processes
that are not initiated by activity of central nervous system. SNpr — preganglionic sympathetic neurons; VNpr — preganglionic vagal neurons.
 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
2006). Moreover, the SNS may modulate immune functions
also by direct regulation of blood flow (Vizi, 1998). Experi-
mental data show that interruption of the SNS in animals has
produced enhancement or suppression of inflammation,
depending on the stage of development at which the system
is ablated, and whether the system is interrupted at a local or
systemic level (Sternberg, 1997).
It is well established that afferent neural pathways in the
vagus nerve participate in the brain-mediated responses to
inflammation (Sternberg, 1997). In addition to this sensory
function of the vagus nerve, an efferent or motor vagus nerve
mechanism has also been described by which acetylcholine,
the principal vagus nerve neurotransmitter, inhibits cytokine
release from resident tissue macrophages (Borovikova et al.,
2000b). The findings show that both pharmacological and
electrical stimulation of the vagus nerve can attenuate the
systemic inflammatory response via cholinergic anti-inflam-
matory pathways (Bernik et al., 2002).
It is necessary to point out that lymphocytes of the various
immunological compartments were found to be equipped
with the key enzymes for the synthesis of both acetylcholine
and catecholamines (Rinner et al., 1998; Kawashima and
Fujii, 2003; Qiu et al., 2004). Therefore effect of acetylcho-
line and catecholamines released by immune cells in para-
crine manner might co-operate/interfere with effect of
neurotransmitters released by autonomic nerves within
immunological compartments.
4. The nervous system and tumorigenesis
4.1. Factors modulating tumorigenesis
Cancer progression is modulated by tumor-related factors
and also by characteristics of the host. Tumor-related factors
include the aggressiveness of a tumor that is determined by
the source tissue, the degree of dedifferentiation, the func-
tionality of apoptosis, DNA repair mechanisms, loss of
contact inhibition, and ability to induce a vascular supply and
to metastasize. Resistance of the host depends on immune
competence and neuroendocrine regulation, which are
subjected to the influence of the brain and behavior (Sephton
and Spiegel, 2003). Furthermore, tumors can shift a hosts'
immune response from immune surveillance to immune
tolerance (Pardoll, 2003).
4.2. The immune system and tumorigenesis
An important role of the immune system is to survey the
body for the development of malignancy and to eliminate
tumors as they arise (Chiplunkar, 2001). Given the fact that
thousands of studies dealt with various aspects of the immune
surveillance of cancer, this review presents only a very
succinct and by no means comprehensive account of the
complex issue. Cell-mediated immune mechanisms together
with humoral mechanism (both mediated by cytokines) are
involved in the modulation of tumor tissue growth (Borish
109
and Steinke, 2003; Hopkins and Rothwell, 1995; Mitra et al.,
2003, Strieter, 2001; Wang et al., 1998). Natural killer (NK)
cells are a type of lymphocytes that posses a variety of
effector mechanisms enabling them to mount a potent anti-
tumor response (Wallace and Smyth, 2005). The function of
NK cells is regulated by a balance between signals trans-
mitted by activating receptors, which recognize ligands on
tumor cells and inhibitory receptors specific for major histo-
compatibility complex class I (MHC-I) molecules (Cerwenka
and Lanier, 2001). Tumor cells frequently lack the co-
stimulatory molecules that drive the development of T-cells
to killer cells (cytotoxic T-cells), and tumors also express less
MHC-I (Bubenik, 2004), making MHC-dependent anti-
tumor immunity more challenging. Dendritic cells (DC)
help to solve this problem, because they help activate
cytotoxic T-cells. DC in the periphery act as antigen-presen-
ting cells, and capture and process tumor antigens, express
co-stimulatory molecules, and secrete cytokines to initiate
cellular immune responses against tumor cells. Therefore DC
have a crucial role in the activation of the immune response
against tumors, especially by activation of NK cells and
cytotoxic T-cells (Banchereau and Steinman, 1998).
Powerful regulators of normal cell behavior are cytokines
which play an important role in the host immune response
against cancer (Mitra et al., 2003). Cytokines modulate tumor
behavior by three important mechanisms including regula-
tion of tumor-associated angiogenesis, activation of a host
tumor-specific immunological response, and direct stimula-
tion of tumor cell proliferation in an autocrine fashion (Arya
et al., 2003; Frederick and Clayman, 2001; Strieter, 2001;
Wang et al., 1998). However, certain pro-inflammatory
cytokines such as IL-1 may also promote tumorigenesis by
enhancing escape from apoptosis, angiogenesis, and metas-
tasis (e.g. Voronov et al., 2003). Thus, while certain arms of
the immune response act against tumor development, others
promote tumorigenesis (Balkwill and Mantovani, 2001).
4.3. The impact of psychosocial factors on cancer incidence
and progression
Several lines of evidence suggest that psychological or
behavioral factors can influence mainly the progression of
cancer (Kiecolt-Glaser and Glaser, 1999; Spiegel and Kato,
1996), though some reviews challenge these conclusions
(Petticrew et al., 2002). Cancer is associated with many cir-
cumstances e.g. fear of death, the side effects of treatment,
cancer pain, the disruption of social activities and social
isolation. Comorbidity of cancer with depression and hope-
lessness is also a common problem. It has been estimated that
half of all cancer patients suffer from psychiatric disorders
usually associated with depression (Spiegel, 1996). Because of
misattribution of depressive symptoms to cancer or its treat-
ment, depression remains often unrecognized and therefore
untreated. Reduced activity of natural killer cell and hyper-
activity of the hypothalamic–pituitary–adrenal (HPA) axis,
which have been observed in major depression (Zorrilla et al.,
110 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
2001), may also promote the disease progression (Spiegel,
1996). A hyperactive HPA axis, due to stress and possible
depression in cancer patients, might influence a disease pro-
gression by two main mechanisms: stimulation of tumor
growth and immunosuppression (Spiegel, 1999). Stimulation
of tumor growth by hypercortisolemia can be explained by
some theories, which include possible stimulation of angio-
genesis, direct stimulation of tumor growth in hormone-
sensitive tumors, and altered gluconeogenesis. The latter in-
volves different responses of tumor cells to glucocorticoid
signals compared to normal cells. This consequently leads to a
selective deprivation of normal cells of metabolic resources
and facilitation of tumor cell growth instead (Spiegel, 1999).
In addition, stress is associated with enhanced secretion of
norepinephrine that may alter NK cell availability and their
function by influencing presence of cell adhesion molecules
on lymphocytes (Spiegel and Kato, 1996). Ben-Eliyahu et al.
(2000) showed that the effects of stress on tumor growth were
mediated by suppression of NK cell activity caused by
catecholamines. Furthermore, activation of β-adrenergic
receptors on tumor cells may promote tumor growth (Antoni
et al., 2006). Another pathway linking psychological factors
with cancer progression is by influencing levels of pro-
inflammatory cytokines. For example, cerebral IL-1 may
mediate the effects of helplessness (Maier and Watkins, 1995)
and cerebral IL-1 can enhance peripheral tumor progression
(Hodgson et al., 1998). Thus, IL-1 may mediate the effects of
helplessness on tumor progression (Argaman et al., 2005).
Recent studies have indicated that psychosocial factors
(e.g. stress) may influence the disease by disruption of
neuroendocrine and immune circadian rhythms. Circadian
rhythm disturbance has also been suggested to be associated
with both cancer incidence and cancer progression. The
effects of circadian system alterations on tumor tissue and in
tumor-bearing animals support this idea. Greater disruption
of circadian systems has also been seen in more advanced
cases of cancer patients. It is hypothesized that circadian
disruption may facilitate tumor growth by several mechan-
isms including abnormalities of immune cell trafficking and
cell proliferation cycles. Another possible pathway includes
direct effects of altered hormone levels on tumor cells and
effects on tumor versus host metabolism (Sephton and
Spiegel, 2003).
The studies, which focus on molecular biology and on the
effects of stress on cellular processes, represent another
possible mechanism by which psychosocial factors may
influence process of cancer. Damage of cellular DNA and
consequent production of abnormal cells is involved in etio-
pathogenesis of tumors. It was shown in animals that stress
exposure was related to lower levels of methyltransferase, an
important DNA repair enzyme induced in response to a car-
cinogen (Heffner et al., 2003). A recent review also points at
the quite consistent effects of stress on DNA-integrity in
animal studies and points at significant associations between
various psychological factors and DNA-damage (Gidron et al.,
2005). Given the central role of DNA-damage in onset of
cancer and in the alterations of established tumors' antigens,
psychological factors may influence tumorigenesis and
progression via affecting DNA-integrity.
There is evidence that psychosocial treatment affects not
only the quality of life in cancer patients, but also patient's
survival (Fawzy et al., 1990; Spiegel, 1995; Spiegel and Kato,
1996; Spiegel and Moore, 1997). Various psychotherapies
improve the course of the disease by reducing depression,
anxiety, fatigue, pain, chemotherapy-induced nausea, vomit-
ing and improving coping skills (Spiegel, 1995, 1996; Spiegel
and Kato, 1996). The impact of psychosocial treatment on
survival as well as on the quality of life, may be mediated by
diverse factors including diet, exercise, sleep or compliance to
medical treatment. On the other hand, psychosocial treatment
may influence disease progression by acting on the immune,
endocrine, and nervous systems (Spiegel and Kato, 1996;
Spiegel, 1999).
Besides providing social support, psychotherapy for
cancer patients consists of emotional expression, cognitive
interventions, imagery techniques and hypnosis (Spiegel,
1995; Spiegel and Moore, 1997). There is evidence that the
coping style and the emotional expression affect survival time
in cancer patients (Spiegel and Kato, 1996). The term
“fighting spirit” is used to describe assertive patients, who
ventilate their emotions directly, including dysphoric affect or
realistic optimism. These patients tend to live longer in
comparison to patients who are more conforming and sub-
missive (Spiegel and Kato, 1996; Spiegel, 1999). Hypnosis
has been found as a psychotherapeutic approach used mainly
to control cancer pain. It is known that such pain can produce
or exacerbate depression, being a common problem in cancer
patients (Spiegel, 1996). It has been shown that the hypnotic
analgesia is more efficacious than acupuncture analgesia in
hypnotizable patients (Spiegel and Moore, 1997).
5. Nervous system and tumorigenesis: questions,
assumptions, and hypotheses
5.1. The tight interconnection between immune and nervous
systems elicits a question whether the brain might modulate
the process of tumorigenesis and if yes, at which level of the
nervous system and in which stage of the tumorigenesis
The following hypotheses have emerged regarding this
issue. It has been suggested that the immune system might
realize sensory functions that can monitor besides infectious
agents also tumor cells (Blalock, 2005). While Blalock has
only indirectly approached the problem of interconnections
between tumor cells, immune system, and the brain, Gidron
et al. (2005) have delineated this relationship more clearly.
Gidron et al. have hypothesized that the brain is informed
about the process of tumorigenesis and responds by modu-
lating processes associated with cancer. They focused on the
connections between inflammatory signals in tumorigenesis
and consequent on interactions between immune signals and
the brain. Recent data show that the brain can induce anti-
 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
inflammatory processes in the immune system directly via
acetylcholine (released from cholinergic pathways of the
efferent vagus) through α-7-nicotinic receptors on macro-
phages (Bernik et al., 2002; Borovikova et al., 2000b; Czura
and Tracey, 2005; Pavlov et al., 2003; Wang et al., 2002b).
Moreover, it has been proven that electrical stimulation of
efferent vagal fibers blunted nuclear NF-κB activation,
decreased the mRNA for TNF, and reduced the circulating
levels of the cytokine (Guarini et al., 2003). It has also been
shown that nuclear NF-κB represents a link between
inflammation and tumorigenesis (Balkwill and Coussens,
2004). Finally, TNF derived from neighboring macrophages
play a pivotal role in the early stages of tumorigenesis
(Pikarsky et al., 2004) and pro-inflammatory cytokines pro-
mote many aspects of late stages in cancer progression (e.g.,
Vronov et al., 2003). Based on these facts, it has been
hypothesized that the vagus nerve might play an important
role in informing the brain about tumorigenesis. Moreover,
the vagus nerve may conduct brain-derived defense processes
against tumors (Gidron et al., 2005).
However, is the brain able to distinguish between
inflammation and tumorigenesis? Presumably, the spectrum
of cytokines and other chemical compounds emerging du-
ring tumorigenesis might provide a sufficient source of
information necessary for the brain to “detect” the presence
of tumor cells in organisms. Compounds released from
tumor cells during their necrosis might represent another
kind of messengers that might inform the brain about
tumorigenesis. Gidron et al. (2005) primarily focused on the
role of the vagus nerve in the proposed mechanisms of the
brain sensing tumorigenesis. Gidron paid more attention to
studies which described findings, that patients with vagot-
omy, as a therapy for gastric ulcers, had a greater risk of lung
and colorectal cancers (Caygill et al., 1991, 1988; Ekbom et
al., 1998; Watt et al., 1984). While data suggest an increased
risk of cancer progression in patients undergoing vagotomy,
it is necessary to take into consideration that other factors
might also play a role in the increased incidence of tumori-
genesis in these patients (for details see Caygill et al., 1991;
Ekbom et al., 1998) such as changes in life-style (resumption
of smoking). Moreover, some controversial results are
obtained from human and experimental studies in animals
(Bayon et al., 2001; Caygill et al., 1993; Fisher et al., 1994;
Lundegardh et al., 1994; Nelson et al., 1992). However,
more direct evidence for Gidron et al. (2005) hypothesis
came from a study demonstrating that animals given a peri-
pheral carcinogen and subsequently undergoing chemical or
surgical vagotomy did not develop reduced food intake
(Bernstein, 1996).
While the above mentioned data seem to be ambiguous,
the convergence of evidence does support the assumption that
bi-directional interconnections between the nervous and
immune systems might constitute an important network for
both sensing and modulation of tumorigenesis by the CNS as
originally predicted by Gidron et al. (2005). However, the
equivocal data from studies dealing with the effects of
111
vagotomy in later cancer development may indicate that the
vagus nerve might represent only one route responsible for
the active interactions between the brain and cancer. We
hypothesize that the SNS, somatic and humoral routes might
also be potentially involved in both monitoring and in
modulating tumorigenesis (Fig. 3; Erin et al., 2004). More-
over, regulation of tumor blood supply by the autonomic
nervous system (Vizi, 1998) might represent an important
factor in modulating tumor growth.
5.2. Could any anti-inflammatory neural pathway take part
in the inhibition of tumor growth?
In recent years it was observed that guanylhydrazone
CNI-1493 has anti-inflammatory effects that may take place
through the vagus nerve (Borovikova et al., 2000a). CNI-
1493 was already studied in the phase I trial in melanoma
and renal cancer patients showing evidence of pharmaco-
logical activity as an inhibitor of TNF production (Atkins et
al., 2001). In the case of melanoma, the interpretation of
these findings in relation to the vagus nerve needs to be taken
with caution since this nerve does not innervate the skin.
Though CNI-1493 activates the efferent vagus fibers, it is
possible that by the effects of the vagus on the HPA-axis, a
systemic suppression of circulating cytokines may have
aided in treating melanoma. Recent data indicate, that anti-
inflammatory pathways of the vagus nerve might be acti-
vated also by occupation of central melanocortin receptors
(e.g. by ACTH, α-melanocyte-stimulating hormone; Guarini
et al., 2004). It thus is possible that therapeutic modulation of
cancer progression via vagomimetic drugs might act at the
level of the CNS and “stimulate” a defense reaction against
tumor cells.
Accumulating data suggest that non-steroidal anti-inflam-
matory drugs (NSAIDs), especially aspirin, prevent cancer
development (Shiff et al., 2003). Interestingly, it was proven,
that NSAIDs modulate peripheral inflammation not only in
regions of inflammation, but also by affecting the CNS
(Catania et al., 1991). Therefore preventive effects of NSAIDs
on cancer development might be potentially mediated also by
its action via the CNS.
5.3. Could a disrupted neural mechanism mean an
increased risk for accelerated tumorigenesis?
Czura and Tracey (2005) suggest that autonomic dys-
function of the cholinergic anti-inflammatory pathways may
predispose some individuals to excessive inflammatory res-
ponses. Whether dysfunction of the neuroendocrine and
immune interaction might predispose to cancer diseases
needs to be investigated.
Similarly, Shanks and Lightman (2001) focused on the
importance of the maternal–neonatal neuro–immune inter-
actions. Some environmental stimuli might alter develop-
ment of these interactions during the intrauterine period.
Shanks and Lightman (2001) suggest that an altered neuro–
112 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116

immune developmental course might contribute to individual
vulnerability to stress-related diseases as well as inflamma-
tion in adulthood. Whether intrauterine alterations of neuro–
immune system interactions might potentially increase
vulnerability to cancer remains to be investigated. A rather
simple manner for measuring such interactions is to test
relations between pro-inflammatory cytokines and heart-rate
variability (HRV), the latter reflecting descending vagal
activity. Normally, an inverse relation exists between such
parameters (Janszky et al., 2004). Future studies may wish to
test whether the magnitude of (inverse) relations between
such parameters predicts risk of cancer.
5.4. Could the nervous system produce and release any
compound of tumor-suppressive significance within tumors?
Interestingly, several peptides (substance P, neuropeptide
Y, adrenomedullin, α-MSH, proenkephalin A) with neural or
neuroendocrine signaling functions have been shown to have
potent antimicrobial activity (Kowalska et al., 2002; Metz-
Boutigue et al., 2003). This discovery suggests that the
nervous system might use these peptides as anti-infective
agents by delivering them rapidly and precisely to the target
sites (Brogden et al., 2005). However, the extent of employ-
ment of these peptides in antimicrobial defense reactions is
not known and needs further experimental supports. Whether
the nervous system might produce substances with potential
tumor-suppressive activity is unknown. However from this
point of view, an interesting molecule is melatonin, with its
possible anti-tumor activity (Kajdaniuk et al., 1999).
Similarly, as mentioned above, the role of brain-derived
oxytocin in halting tumor progression also needs to be further
examined.
5.5. Could any of the functional techniques (fMRI, PET) be
able to detect an altered response in certain important brain
areas (NTS, PVN, SCHN) in cancer patients, especially
after exposing them to experimental stimuli?
The peripheral nerves may represent one of the most
important routes for transmission of information about tu-
morigenesis. In general, tumorigenesis is a long-lasting pro-
cess and it may potentially induce changes in the activity of
some brain regions. For example, the nucleus of the solitary
tract (NTS), which relays visceral information, might be
modulated from peripheral tumors. Other regions may be the
hypothalamic paraventricular (PVN) and suprachiasmatic
(SCHN) nuclei. The PVN represents the coordinating center

Fig. 3. Presumed interaction between nervous, endocrine, immune system, and tumor cells. Tumor cells release compounds (e.g. cytokines, growth factors) that
might influence brain function. Whether the nervous system releases some compounds that might directly modulate tumor growth remains unclear. Bi-directional
interconnections between tumor and immune cells and consequent interconnections between the nervous and immune systems might constitute a base for
monitoring and modulation of tumorigenesis by brain. Sentinel cells (tissue fibroblasts) may also play an important role in modulating inflammatory processes
and tumorigenesis (Silzle et al., 2004; Tlsty and Hein, 2001) and might process and transmit information from the immune system and tumor cells to the central
nervous system. Tumor cells growth might be influenced by the endocrine system and vice versa. Therefore possible pathways for modulation of tumorigenesis
might include bi-directional interconnections between the brain, endocrine system and tumor cells.
 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
of autonomic, endocrine, and immune systems. SCN is one of
the key regulators of the circadian rhythm. Disruption of the
circadian rhythm might also participate in tumorigenesis
(Filipski et al., 2002; Sephton and Spiegel, 2003). For
example, melatonin, a hormone of importance in circadian
rhythms, influences the growth of spontaneous and induced
tumors in animals. While data in humans are conflicting, the
majority of reports point toward protective actions of
melatonin (Brzezinski, 1997). Whether possible alteration
of NTS neuron activity influences also the processing of
gustatory information and therefore the change in quality or
quantity of food intake in patients with cancer, is unclear.
Similarly, possible interference between cancer therapy and
processing of information in the above-mentioned and other
brain regions needs further investigation. Future studies need
to examine whether the sensitivity and responses of such
brain regions to tumor-related inflammatory signals may play
a role in the early and later stages of cancer progression.
5.6. What is the role of the CNS and tumor interactions in
alternative therapeutic approaches?
Pavlov et al. (2003) suggest a role of alternative thera-
peutic approaches (e.g. hypnosis, biofeedback, acupuncture,
and even Pavlovian conditioning) in modulation of inflam-
matory diseases. On the basis of data reviewed in this article,
it can be suggested that all of these methods can potentially
modulate also inflammatory processes connected with
progression of cancer via modulation of CNS–tumor inter-
actions since these therapies influence the SNS and vagal
activity (e.g., Infante et al., 2001; Bernardi et al., 2001).
Focused experimental work is necessary to answer all
these questions. The possibility that the brain is informed
about tumors in the body is exciting and might open new
research areas. Cancer research focuses in this new area might
bring important data not only about etiopathogenesis, but also
data that might improve diagnosis and therapy of cancer.
6. Conclusion
In this review, an attempt was made to highlight certain
facts indicating that deeper understanding of the immuno-
regulatory role of the brain and sensory functions of the
immune system might dramatically modify our knowledge
regarding the neural–endocrine–immune interactions rele-
vant to the pathophysiology of tumorigenesis, with clinical
implications for medicine.
While the classical five senses inform us about the changes
in the external world, it is under the speculation that the
information detected by the vagal visceral receptors (Zagon,
2001) or the immune system (Andersson, 2005; Blalock,
2005; Ferencik and Stvrtinova, 1997) might form a “sixth
sense”. Whether sensing of tumorigenesis might be a part of
this “sixth sense” combining visceral perception by the vagus
nerve with immune system signals, still remains unclear.
Although, this article summarizes data supporting the hy-
113
pothesis, that the brain might posses the capability to detect
tumorigenesis and buttress defensive mechanisms against
cancer progression (Gidron et al., 2005), there are not enough
data, at present time, to completely substantiate this hypo-
thesis. Therefore, further research is necessary to illuminate
the possibility that the brain might “know” about tumorigen-
esis in the body and modulate its progression, via several
neuroendocrine routes.
Acknowledgement
The authors thank MD. Peter Ujhazy, PhD for valuable
contributions. This work was supported by Grant of
Comenius University UK/40/2006.
References
Ádám, G., 1998. Theoretical considerations. In: Ádám, G. (Ed.), Visceral
Perception. Understanding Internal Cognition. Plenom Press, New York,
pp. 3–27.
Almawi, W.Y., Melemedjian, O.K., Rieder, M.J., 1999. An alternate
mechanism of glucocorticoid anti-proliferative effect: promotion of a
Th2 cytokine-secreting profile. Clin. Transplant. 13, 365–374.
Andersson, J., 2005. The inflammatory reflex—introduction. J. Intern. Med.
257, 122–125.
Antoni, M.H., Lutgendorf, S.K., Cole, S.W., Dhabhar, F.S., Sephton, S.E.,
McDonald, P.G., Stefanek, M., Sood, A.K., 2006. The influence of bio-
behavioural factors on tumour biology: pathways and mechanisms. Nat.
Rev., Cancer 6, 240–248.
Argaman, M., Gidron, Y., Ariad, S., 2005. Interleukin-1 may link
helplessness–hopelessness with cancer progression: a proposed model.
Int. J. Behav. Med. 12, 161–170.
Arya, M., Patel, H.R., Williamson, M., 2003. Chemokines: key players in
cancer. Curr. Med. Res. Opin. 19, 557–564.
Atkins, M.B., Redman, B., Mier, J., Gollob, J., Weber, J., Sosman, J.,
MacPherson, B.L., Plasse, T., 2001. A phase I study of CNI-1493, an
inhibitor of cytokine release, in combination with high-dose interleukin-2
in patients with renal cancer and melanoma. Clin. Cancer Res. 7, 486–492.
Balkwill, F., Coussens, L.M., 2004. Cancer: an inflammatory link. Nature
431, 405–406.
Balkwill, F., Mantovani, A., 2001. Inflammation and cancer: back to
Virchow? Lancet 357, 539–545.
Banchereau, J., Steinman, R.M., 1998. Dendritic cells and the control of
immunity. Nature 392, 245–252.
Banks, W.A., Kastin, A.J., Gutierrez, E.G., 1993. Interleukin-1 alpha in
blood has direct access to cortical brain cells. Neurosci. Lett. 163, 41–44.
Basu, S., Dasgupta, P.S., 2000. Dopamine, a neurotransmitter, influences the
immune system. J. Neuroimmunol. 102, 113–124.
Bayon, L.A.M., Landa, G.I., Alcalde, E.J., Rodriguez, D.S., Ortega, M.L.,
Balibrea, C.J.L., 2001. Colonic carcinogenesis in vagotomyzed rats.
Rev. Esp. Enferm. Dig. 93, 576–586.
Ben-Eliyahu, S., Shakhar, G., Page, G.G., Stefanski, V., Shakhar, K., 2000.
Suppression of NK cell activity and of resistance to metastasis by stress:
a role for adrenal catecholamines and beta-adrenoceptors. Neuroimmu-
nomodulation 8, 154–164.
Berczi, I., 1994. The role of the growth and lactogenic hormone family in
immune function. Neuroimmunomodulation 1, 201–216.
Berczi, I., 1997. Pituitary hormones and immune function. Acta Paediatr.
423, 70–75.
Berczi, I., 2001. Neuroimmune biology — an introduction. In: Berczi, I.,
Gorezynski, R.M. (Eds.), New Foundation of Biology. Elsevier Science,
Amsterdam, pp. 3–45.
Bernardi, L., Sleight, P., Bandinelli, G., Cencetti, S., Fattorini, L.,
Wdowczyc-Szulc, J., Lagi, A., 2001. Effect of rosary prayer and yoga
114 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
mantras on autonomic cardiovascular rhythms: comparative study. BMJ
323, 1446–1449.
Bernik, T.R., Friedman, S.G., Ochani, M., DiRaimo, R., Ulloa, L., Yang, H.,
Sudan, S., Czura, C.J., Ivanova, S.M., Tracey, K.J., 2002. Pharmaco-
logical stimulation of the cholinergic antiinflammatory pathway. J. Exp.
Med. 195, 781–788.
Bernstein, I.L., 1996. Neutral mediation of food aversions and anorexia
induced by tumor necrosis factor and tumors. Neurosci. Biobehav. Rev.
20, 177–181.
Berthoud, H.R., 2004. Anatomy and function of sensory hepatic nerves.
Anat. Rec. A. Discov. Mol. Cell. Evol. Biol. 280, 827–835.
Besedovsky, H.O., del Rey, A., 1996. Immune–neuro–endocrine interac-
tions: facts and hypotheses. Endocr. Rev. 17, 64–102.
Blalock, J.E., 1984. The immune system as a sensory organ. J. Immunol.
132, 1067–1070.
Blalock, J.E., 1994. The syntax of immune–neuroendocrine communica-
tion. Immunol. Today 15, 504–511.
Blalock, J.E., 2002. Harnessing a neural–immune circuit to control
inflammation and shock. J. Exp. Med. 195, F25–F28.
Blalock, J.E., 2005. The immune system as the sixth sense. J. Intern. Med.
257, 126–138.
Borish, L.C., Steinke, J.W., 2003. 2. Cytokines and chemokines. J. Allergy
Clin. Immunol. 111, S460–S475.
Borovikova, L.V., Ivanova, S., Nardi, D., Zhang, M., Yang, H., Ombrellino, M.,
Tracey, K.J., 2000a. Role of vagus nerve signaling in CNI-1493-mediated
suppression of acute inflammation. Auton. Neurosci. 85, 141–147.
Borovikova, L.V., Ivanova, S., Nardi, D., Zhang, M., Yang, H., Ombrellino,
M., Tracey, K.J., 2000b. Vagus nerve stimulation attenuates the systemic
inflammatory response to endotoxin. Nature 405, 458–462.
Brogden, K.A., Guthmiller, J.M., Salzet, M., Zasloff, M., 2005. The nervous
system and innate immunity: the neuropeptide connection. Nat.
Immunol. 6, 558–564.
Brzezinski, A., 1997. Melatonin in humans. N. Engl. J. Med. 336, 186–195.
Bubenik, J., 2004. MHC class I down-regulation: tumour escape from
immune surveillance? Int. J. Oncol. 25, 487–491 (review).
Buckley, C.D., Pilling, D., Lord, J.M., Akbar, A.N., Scheel-Toellner, D.,
Salmon, M., 2001. Fibroblasts regulate the switch from acute resolving
to chronic persistent inflammation. Trends Immunol. 22, 199–204.
Buller, K.M., 2001. Role of circumventricular organs in pro-inflammatory
cytokine-induced activation of the hypothalamic–pituitary–adrenal axis.
Clin. Exp. Pharmacol. Physiol. 28, 581–589.
Cassoni, P., Sapino, A., Marrocco, T., Chini, B., Bussolati, G., 2004.
Oxytocin and oxytocin receptors in cancer cells and proliferation.
J. Neuroendocrinol. 16, 362–364.
Catania, A., Arnold, J., Macaluso, A., Hiltz, M.E., Lipton, J.M., 1991.
Inhibition of acute inflammation in the periphery by central action of
salicylates. Proc. Natl. Acad. Sci. U. S. A. 88, 8544–8547.
Caygill, C.P., Hill, M.J., Kirkham, J.S., Northfield, T.C., 1988. Mortality
from colorectal and breast cancer in gastric-surgery patients. Int. J.
Colorectal Dis. 3, 144–148.
Caygill, C.P., Knowles, R.L., Hall, R., 1991. Increased risk of cancer
mortality after vagotomy for peptic ulcer: a preliminary analysis. Eur. J.
Cancer Prev. 1, 35–37.
Caygill, C.P., Hill, M.J., Kirkham, J.S., Northfield, T.C., 1993. Oesopha-
geal cancer in gastric surgery patients. Ital. J. Gastroenterol. 25,
168–170.
Cerwenka, A., Lanier, L.L., 2001. Natural killer cells, viruses and cancer.
Nat. Rev., Immunol. 1, 41–49.
Chaplin, D.D., 2003. 1. Overview of the immune response. J. Allergy Clin.
Immunol. 111, S442–S459.
Chiplunkar, S.V., 2001. The immune system and cancer. Curr. Sci. 81,
542–548.
Cottrell, G.T., Ferguson, A.V., 2004. Sensory circumventricular organs:
central roles in integrated autonomic regulation. Regul. Pept. 117,
11–23.
Czura, C.J., Tracey, K.J., 2005. Autonomic neural regulation of immunity.
J. Intern. Med. 257, 156–166.
Dantzer, R., Konsman, J.P., Bluthe, R.M., Kelley, K.W., 2000. Neural and
humoral pathways of communication from the immune system to the
brain: parallel or convergent? Auton. Neurosci. 85, 60–65.
Dardenne, M., Savino, W., 1994. Control of thymus physiology by peptidic
hormones and neuropeptides. Immunol. Today 15, 518–523.
Delves, P.J., Roitt, I.M., 2000a. The immune system. First of two parts.
N. Engl. J. Med. 343, 37–49.
Delves, P.J., Roitt, I.M., 2000b. The immune system. Second of two parts.
N. Engl. J. Med. 343, 108–117.
Denes, A., Boldogkoi, Z., Uhereczky, G., Hornyak, A., Rusvai, M.,
Palkovits, M., Kovacs, K.J., 2005. Central autonomic control of the bone
marrow: multisynaptic tract tracing by recombinant pseudorabies virus.
Neuroscience 134, 947–963.
Downing, J.E., Miyan, J.A., 2000. Neural immunoregulation: emerging
roles for nerves in immune homeostasis and disease. Immunol. Today
21, 281–289.
Ek, M., Kurosawa, M., Lundeberg, T., Ericsson, A., 1998. Activation of
vagal afferents after intravenous injection of interleukin-1beta: role of
endogenous prostaglandins. J. Neurosci. 18, 9471–9479.
Ekbom, A., Lundegardh, G., McLaughlin, J.K., Nyren, O., 1998. Relation of
vagotomy to subsequent risk of lung cancer: population based cohort
study. BMJ 316, 518–519.
Elenkov, I.J., Hasko, G., Kovacs, K.J., Vizi, E.S., 1995. Modulation of
lipopolysaccharide-induced tumor necrosis factor-alpha production by
selective alpha- and beta-adrenergic drugs in mice. J. Neuroimmunol.
61, 123–131.
Elenkov, I.J., Wilder, R.L., Chrousos, G.P., Vizi, E.S., 2000. The
sympathetic nerve—an integrative interface between two supersystems:
the brain and the immune system. Pharmacol. Rev. 52, 595–638.
Elmquist, J.K., Scammell, T.E., Saper, C.B., 1997. Mechanisms of CNS
response to systemic immune challenge: the febrile response. Trends
Neurosci. 20, 565–570.
Ericsson, A., Liu, C., Hart, R.P., Sawchenko, P.E., 1995. Type 1 interleukin-
1 receptor in the rat brain: distribution, regulation, and relationship to
sites of IL-1-induced cellular activation. J. Comp. Neurol. 361,
681–698.
Erin, N., Boyer, P.J., Bonneau, R.H., Clawson, G.A., Welch, D.R., 2004.
Capsaicin-mediated denervation of sensory neurons promotes mammary
tumor metastasis to lung and heart. Anticancer Res. 24, 1003–1009.
Fabris, N., Mocchegiani, E., Provinciali, M., 1995. Pituitary–thyroid axis
and immune system: a reciprocal neuroendocrine–immune interaction.
Horm. Res. 43, 29–38.
Fawzy, F.I., Kemeny, M.E., Fawzy, N.W., Elashoff, R., Morton, D., Cousins,
N., Fahey, J.L., 1990. A structured psychiatric intervention for cancer
patients. II. Changes over time in immunological measures. Arch. Gen.
Psychiatry 47, 729–735.
Ferencik, M., Stvrtinova, V., 1997. Is the immune system our sixth sense?
Relation between the immune and neuroendocrine systems. Bratisl. Lek.
Listy 98, 187–198.
Ferguson, A.V., Bains, J.S., 1996. Electrophysiology of the circumven-
tricular organs. Front. Neuroendocrinol. 17, 440–475.
Filipski, E., King, V.M., Li, X., Granda, T.G., Mormont, M.C., Liu, X.,
Claustrat, B., Hastings, M.H., Levi, F., 2002. Host circadian clock as a
control point in tumor progression. J. Natl. Cancer Inst. 94, 690–697.
Fisher, S.G., Davis, F., Nelson, R., Weber, L., Haenszel, W., 1994. Large
bowel cancer following gastric surgery for benign disease: a cohort
study. Am. J. Epidemiol. 139, 684–692.
Frederick, M.J., Clayman, G.L., 2001. Chemokines in cancer. Expert Rev.
Mol. Med. 2001, 1–18.
Ganong, W.F., 2000. Circumventricular organs: definition and role in the
regulation of endocrine and autonomic function. Clin. Exp. Pharmacol.
Physiol. 27, 422–427.
Gidron, Y., Perry, H., Glennie, M., 2005. Does the vagus nerve inform the
brain about preclinical tumours and modulate them? Lancet Oncol. 6,
245–248.
Goehler, L.E., Relton, J.K., Dripps, D., Kiechle, R., Tartaglia, N., Maier, S.F.,
Watkins, L.R., 1997. Vagal paraganglia bind biotinylated interleukin-1
 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
receptor antagonist: a possible mechanism for immune-to-brain commu-
nication. Brain Res. Bull. 43, 357–364.
Goehler, L.E., Gaykema, R.P., Hammack, S.E., Maier, S.F., Watkins, L.R.,
1998. Interleukin-1 induces c-Fos immunoreactivity in primary afferent
neurons of the vagus nerve. Brain Res. 804, 306–310.
Goehler, L.E., Gaykema, R.P., Nguyen, K.T., Lee, J.E., Tilders, F.J., Maier,
S.F., Watkins, L.R., 1999. Interleukin-1beta in immune cells of the
abdominal vagus nerve: a link between the immune and nervous
systems? J. Neurosci. 19, 2799–2806.
Goehler, L.E., Gaykema, R.P., Hansen, M.K., Anderson, K., Maier, S.F.,
Watkins, L.R., 2000. Vagal immune-to-brain communication: a visceral
chemosensory pathway. Auton. Neurosci. 85, 49–59.
Guarini, S., Altavilla, D., Cainazzo, M.M., Giuliani, D., Bigiani, A., Marini,
H., Squadrito, G., Minutoli, L., Bertolini, A., Marini, R., Adamo, E.B.,
Venuti, F.S., Squadrito, F., 2003. Efferent vagal fibre stimulation blunts
nuclear factor-kappaB activation and protects against hypovolemic
hemorrhagic shock. Circulation 107, 1189–1194.
Guarini, S., Cainazzo, M.M., Giuliani, D., Mioni, C., Altavilla, D., Marini, H.,
Bigiani, A., Ghiaroni, V., Passaniti, M., Leone, S., Bazzani, C., Caputi, A.
P., Squadrito, F., Bertolini, A., 2004. Adrenocorticotropin reverses
hemorrhagic shock in anesthetized rats through the rapid activation of a
vagal anti-inflammatory pathway. Cardiovasc. Res. 63, 357–365.
Hansen, M.K., Daniels, S., Goehler, L.E., Gaykema, R.P., Maier, S.F., Watkins,
L.R., 2000. Subdiaphragmatic vagotomy does not block intraperitoneal
lipopolysaccharide-induced fever. Auton. Neurosci. 85, 83–87.
Harre, E.M., Roth, J., Pehl, U., Kueth, M., Gerstberger, R., Hubschle, T.,
2002. Selected contribution: role of IL-6 in LPS-induced nuclear STAT3
translocation in sensory circumventricular organs during fever in rats.
J. Appl. Physiol. 92, 2657–2666.
Hasko, G., Szabo, C., 1998. Regulation of cytokine and chemokine
production by transmitters and co-transmitters of the autonomic nervous
system. Biochem. Pharmacol. 56, 1079–1087.
Heffner, K.L., Loving, T.J., Robles, T.F., Kiecolt-Glaser, J.K., 2003.
Examining psychosocial factors related to cancer incidence and
progression: in search of the silver lining. Brain Behav. Immun. 17,
109–111.
Hermann, G.E, Holmes, G.M, Rogers, R.C., 2005. TNF(alpha) modulation
of visceral and spinal sensory processing. Curr. Pharm. 11, 1391–1409.
Hodgson, D.M., Yirmiya, R., Chiappelli, F., Taylor, A.N., 1998.
Intracerebral HIV glycoprotein (gp120) enhances tumor metastasis via
centrally released interleukin-1. Brain Res. 781, 244–251.
Hopkins, S.J., Rothwell, N.J., 1995. Cytokines and the nervous system.
I: expression and recognition. Trends Neurosci. 18, 83–88.
Infante, J.R., Torres-Avisbal, M., Pinel, P., Vallejo, J.A., Peran, F., Gonzalez,
F., Contreras, P., Pacheco, C., Roldan, A., Latre, J.M., 2001.
Catecholamine levels in practitioners of the transcendental meditation
technique. Physiol. Behav. 72, 141–146.
Janszky, I., Ericson, M., Lekander, M., Blom, M., Buhlin, K., Georgiades,
A., Ahnve, S., 2004. Inflammatory markers and heart rate variability in
women with coronary heart disease. J. Intern. Med. 256, 421–428.
Kajdaniuk, D., Marek, B., Kos-Kudta, B., Ciesielska-Kopacz, N., Buntner,
B., 1999. Oncostatic effect of melatonin action — facts and hypotheses.
Med. Sci. Monit. 5, RA350–RA356.
Katayama, Y., Battista, M., Kao, W.M., Hidalgo, A., Peired, A.J., Thomas, S.A.,
Frenette, P.S., 2006. Signals from the sympathetic nervous system regulate
hematopoietic stem cell egress from bone marrow. Cell 124, 407–421.
Kaufman, J., Graf, B.A., Leung, E.C., Pollock, S.J., Koumas, L., Reddy, S.Y.,
Blieden, T.M., Smith, T.J., Phipps, R.P., 2001. Fibroblasts as sentinel
cells: role of the CDcd40–CDcd40 ligand system in fibroblast activation
and lung inflammation and fibrosis. Chest 120, 53S–55S.
Kawashima, K., Fujii, T., 2003. The lymphocytic cholinergic system and its
biological function. Life Sci. 72, 2101–2109.
Kiecolt-Glaser, J.K., Glaser, R., 1999. Psychoneuroimmunology and cancer:
fact or fiction? Eur. J. Cancer 35, 1603–1607.
Konsman, J.P., Parnet, P., Dantzer, R., 2002. Cytokine-induced sickness
behaviour: mechanisms and implications. Trends Neurosci. 25,
154–159.
115
Kowalska, K., Carr, D.B., Lipkowski, A.W., 2002. Direct antimicrobial
properties of substance P. Life Sci. 71, 747–750.
Kvetnoy, I.M., 2002. Neuroimmunoendocrinology: where is the field for
study? Neuro. Endocrinol. Lett. 23, 119–120.
Licinio, J., Wong, M.L., 1997. Pathways and mechanisms for cytokine
signaling of the central nervous system. J. Clin. Invest. 100, 2941–2947.
Lundegardh, G., Ekbom, A., McLaughlin, J.K., Nyren, O., 1994. Gastric
cancer risk after vagotomy. Gut 35, 946–949.
Maier, S.F., Watkins, L.R., 1995. Intracerebroventricular interleukin-1 receptor
antagonist blocks the enhancement of fear conditioning and interference
with escape produced by inescapable shock. Brain Res. 695, 279–282.
Maier, S.F., Goehler, L.E., Fleshner, M., Watkins, L.R., 1998. The role of the
vagus nerve in cytokine-to-brain communication. Ann. N.Y. Acad. Sci.
840, 289–300.
Manna, S.K., Aggarwal, B.B., 1998. Alpha-melanocyte-stimulating hor-
mone inhibits the nuclear transcription factor NF-kappa B activation
induced by various inflammatory agents. J. Immunol. 161, 2873–2880.
Mantovani, A., 1999. The chemokine system: redundancy for robust
outputs. Immunol. Today 20, 254–257.
Metz-Boutigue, M.H., Goumon, Y., Strub, J.M., Lugardon, K., Aunis, D.,
2003. Antimicrobial chromogranins and proenkephalin-A-derived
peptides: Antibacterial and antifungal activities of chromogranins
and proenkephalin-A-derived peptides. Ann. N.Y. Acad. Sci. 992,
168–178.
Mitra, R., Singh, S., Khar, A., 2003. Antitumour immune responses. Expert
Rev. Mol. Med. 2003, 1–22.
Nadeau, S., Rivest, S., 1999. Effects of circulating tumor necrosis factor on
the neuronal activity and expression of the genes encoding the tumor
necrosis factor receptors (p55 and p75) in the rat brain: a view from the
blood–brain barrier. Neuroscience 93, 1449–1464.
Nelson, R.L., Briley, S., Vaz, O.P., Abcarian, H., 1992. The effect of
vagotomy and pyloroplasty on colorectal tumor induction in the rat.
J. Surg. Oncol. 51, 281–286.
Paintal, A.S., 1973. Vagal sensory receptors and their reflex effects. Physiol.
Rev. 53, 159–227.
Pardoll, D., 2003. Does the immune system see tumors as foreign or self?
Annu. Rev. Immunol. 21, 807–839.
Parkin, J., Cohen, B., 2001. An overview of the immune system. Lancet 357,
1777–1789.
Pavlov, V.A., Wang, H., Czura, C.J., Friedman, S.G., Tracey, K.J., 2003. The
cholinergic anti-inflammatory pathway: a missing link in neuroimmu-
nomodulation. Mol. Med. 9, 125–134.
Perry, V.H., 2004. The impact of systemic inflammation on brain
inflammation. ACNR 4, 8–9.
Petrovsky, N., 2001. Towards a unified model of neuroendocrine–immune
interaction. Immunol. Cell Biol. 79, 350–357.
Petticrew, M., Bell, R., Hunter, D., 2002. Influence of psychological coping
on survival and recurrence in people with cancer: systematic review.
BMJ 325, 1066.
Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S.,
Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., Ben-Neriah, Y., 2004.
NF-kappaβ functions as a tumour promoter in inflammation-associated
cancer. Nature 431, 461–466.
Qiu, Y.H., Peng, Y.P., Jiang, J.M., Wang, J.J., 2004. Expression of
tyrosine hydroxylase in lymphocytes and effect of endogenous
catecholamines on lymphocyte function. Neuroimmunomodulation
11, 75–83.
Quan, N., Herkenham, M., 2002. Connecting cytokines and brain: a review
of current issues. Histol. Histopathol. 17, 273–288.
Rinner, I., Felsner, P., Liebmann, P.M., Hofer, D., Wolfler, A., Globerson,
A., Schauenstein, K., 1998. Adrenergic/cholinergic immunomodulation
in the rat model—in vivo veritas? Dev. Immunol. 6, 245–252.
Rivest, S., 2001. How circulating cytokines trigger the neural circuits that
control the hypothalamic–pituitary–adrenal axis. Psychoneuroendocri-
nology 26, 761–788.
Romanovsky, A.A., Ivanov, A.I., Szekely, M., 2000. Neural route of
pyrogen signaling to the brain. Clin. Infect. Dis. 31, S162–S167.
116 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116
Rook, G.A., Lightman, S.L., Heijnen, C.J., 2002. Can nerve damage disrupt
neuroendocrine immune homeostasis? Leprosy as a case in point. Trends
Immunol. 23, 18–22.
Roth, J., De Souza, G.E., 2001. Fever induction pathways: evidence from
responses to systemic or local cytokine formation. Braz. J. Med. Biol.
Res. 34, 301–314.
Roth, J., Harre, E.M., Rummel, C., Gerstberger, R., Hubschle, T., 2004.
Signaling the brain in systemic inflammation: role of sensory
circumventricular organs. Front. Biosci. 9, 290–300.
Rothwell, N.J., Hopkins, S.J., 1995. Cytokines and the nervous system II:
actions and mechanisms of action. Trends Neurosci. 18, 130–136.
Savino, W., Dardenne, M., 1995. Immune–neuroendocrine interactions.
Immunol. Today 16, 318–322.
Sephton, S., Spiegel, D., 2003. Circadian disruption in cancer: a
neuroendocrine–immune pathway from stress to disease? Brain Behav.
Immun. 17, 321–328.
Shanks, N., Lightman, S.L., 2001. The maternal–neonatal neuro–immune
interface: are there long-term implications for inflammatory or stress-
related disease? J. Clin. Invest. 108, 1567–1573.
Shepherd, A.J., Downing, J.E., Miyan, J.A., 2005. Without nerves,
immunology remains incomplete—in vivo veritas. Immunology 116,
145–163.
Shiff, S.J., Shivaprasad, P., Santini, D.L., 2003. Cyclooxygenase inhibitors:
drugs for cancer prevention. Curr. Opin. Pharmacol. 3, 352–361.
Silzle, T., Randolph, G.J., Kreutz, M., Kunz-Schughart, L.A., 2004. The
fibroblast: sentinel cell and local immune modulator in tumor tissue. Int.
J. Cancer 108, 173–180.
Smith, R.S., Smith, T.J., Blieden, T.M., Phipps, R.P., 1997. Fibroblasts as
sentinel cells. Synthesis of chemokines and regulation of inflammation.
Am. J. Pathol. 151, 317–322.
Spiegel, D., 1995. Essentials of psychotherapeutic intervention for cancer
patients. Support. Care Cancer 3, 252–256.
Spiegel, D., 1996. Cancer and depression. Br. J. Psychiatry (Suppl. 109),
16.
Spiegel, D., 1999. Embodying the mind in psychooncology research. Adv.
Mind-Body Med. 15, 267–273 (discussion 275–281).
Spiegel, D., Kato, P.M., 1996. Psychosocial influences on cancer incidence
and progression. Harv. Rev. Psychiatry 4, 10–26.
Spiegel, D., Moore, R., 1997. Imagery and hypnosis in the treatment of
cancer patients. Oncology 11, 1179–1189 (discussion 1189–1195).
Sternberg, E.M., 1997. Neural–immune interactions in health and disease.
J. Clin. Invest. 100, 2641–2647.
Stevens-Felten, S.Y., Bellinger, D.L., 1997. Noradrenergic and peptidergic
innervation of lymphoid organs. Chem. Immunol. 69, 99–131.
Straub, R.H., Westermann, J., Scholmerich, J., Falk, W., 1998. Dialogue
between the CNS and the immune system in lymphoid organs. Immunol.
Today 19, 409–413.
Strieter, R.M., 2001. Chemokines: not just leukocyte chemoattractants in the
promotion of cancer. Nat. Immunol. 2, 285–286.
Szelenyi, J., 2001. Cytokines and the central nervous system. Brain Res.
Bull. 54, 329–338.
Tlsty, T.D., Hein, P.W., 2001. Know thy neighbor: stromal cells can
contribute oncogenic signals. Curr. Opin. Genet. Dev. 11, 54–59.
Tracey, K.J., 2002. The inflammatory reflex. Nature 420, 853–859.
Turnbull, A.V., Rivier, C.L., 1999. Regulation of the hypothalamic–
pituitary–adrenal axis by cytokines: actions and mechanisms of action.
Physiol. Rev. 79, 1–71.
Turrin, N.P., Rivest, S., 2004. Unraveling the molecular details involved in
the intimate link between the immune and neuroendocrine systems. Exp.
Biol. Med. 229, 996–1006.
Vallieres, L., Rivest, S., 1997. Regulation of the genes encoding interleukin-
6, its receptor, and gp130 in the rat brain in response to the immune
activator lipopolysaccharide and the proinflammatory cytokine inter-
leukin-1beta. J. Neurochem. 69, 1668–1683.
Vamvakopoulos, N.C., Chrousos, G.P., 1994. Hormonal regulation of
human corticotropin-releasing hormone gene expression: implications
for the stress response and immune/inflammatory reaction. Endocr. Rev.
15, 409–420.
Vizi, E.S., 1998. Receptor-mediated local fine-tuning by noradrenergic
innervation of neuroendocrine and immune systems. Ann. N.Y. Acad.
Sci. 851, 388–396.
Vizi, E.S., Orso, E., Osipenko, O.N., Hasko, G., Elenkov, I.J., 1995.
Neurochemical, electrophysiological and immunocytochemical evi-
dence for a noradrenergic link between the sympathetic nervous system
and thymocytes. Neuroscience 68, 1263–1276.
Voronov, E., Shouval, D.S., Krelin, Y., Cagnano, E., Benharroch, D.,
Iwakura, Y., Dinarello, C.A., Apte, R.N., 2003. IL-1 is required for
tumor invasiveness and angiogenesis. Proc. Natl. Acad. Sci. USA 100,
2645–2650.
Wallace, M.E., Smyth, M.J., 2005. The role of natural killer cells in tumor
control-effectors and regulators of adaptive immunity. Springer Semin.
Immunopathol. 27, 49–64.
Wang, J.M., Deng, X., Gong, W., Su, S., 1998. Chemokines and their role in
tumor growth and metastasis. J. Immunol. Methods 220, 1–17.
Wang, X., Wang, B.R., Duan, X.L., Zhang, P., Ding, Y.Q., Jia, Y., Jiao, X.Y.,
Ju, G., 2002a. Strong expression of interleukin-1 receptor type I in the rat
carotid body. J. Histochem. Cytochem. 50, 1677–1684.
Wang, X., Wang, B.R., Zhang, X.J., Xu, Z., Ding, Y.Q., Ju, G., 2002b.
Evidences for vagus nerve in maintenance of immune balance and
transmission of immune information from gut to brain in STM-infected
rats. World J. Gastroenterol. 8, 540–545.
Watkins, L.R., Maier, S.F., Goehler, L.E., 1995. Cytokine-to-brain
communication: a review and analysis of alternative mechanisms. Life
Sci. 57, 1011–1026.
Watt, P.C., Patterson, C.C., Kennedy, T.L., 1984. Late mortality after
vagotomy and drainage for duodenal ulcer. Br. Med. J. (Clin. Res. Ed.)
288, 1335–1338.
Weigent, D.A., Blalock, J.E., 1987. Interactions between the neuroendocrine
and immune systems: common hormones and receptors. Immunol. Rev.
100, 79–108.
Yang, H., Wang, L., Ju, G., 1997. Evidence for hypothalamic paraventricular
nucleus as an integrative center of neuroimmunomodulation. Neuroim-
munomodulation 4, 120–127.
Zagon, A., 2001. Does the vagus nerve mediate the sixth sense? Trends
Neurosci. 24, 671–673.
Zorrilla, E.P., Luborsky, L., McKay, J.R., Rosenthal, R., Houldin, A., Tax,
A., McCorkle, R., Seligman, D.A., Schmidt, K., 2001. The
relationship of depression and stressors to immunological assays: a
meta-analytic review. Brain Behav. Immun. 15, 199–226.
Further readings
Bovbjerg, D.H., 1991. Psychoneuroimmunology. Implications for oncolo-
gy? Cancer 67, 828–832.
Molina, P.E., 2005. Neurobiology of the stress response: contribution of the
sympathetic nervous system to the neuroimmune axis in traumatic
injury. Shock 24, 3–10.
Pert, C.B., Dreher, H.E., Ruff, M.R., 1998. The psychosomatic network:
foundations of mind-body medicine. Altern. Ther. Health Med. 4,
30–41.
Plata-Salaman, C.R., 1991. Immunoregulators in the nervous system.
Neurosci. Biobehav. Rev. 15, 185–215.
Tracey, K.J., Czura, C.J., Ivanova, S., 2001. Mind over immunity. FASEB J.
15, 1575–1576.
Yabuuchi, K., Minami, M., Katsumata, S., Satoh, M., 1994. Localization of
type I interleukin-1 receptor mRNA in the rat brain. Brain Res. Mol.
Brain Res. 27, 27–36.