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Current Drug Targets - Inflammation & Allergy, 2005, 4, 471-479 471

Nitric Oxide Production and Signaling in Inflammation


Riku Korhonen, Aleksi Lahti, Hannu Kankaanranta and Eeva Moilanen*

The Immunopharmacology Research Group, University of Tampere Medical School and Research Unit, Tampere
University Hospital, Tampere, Finland
Abstract: Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. It possesses cytotoxic properties that are aimed
against pathogenic microbes, but it can also have damaging effects on host tissues. NO reacts with soluble guanylate cyclase to form cyclic
guanosine monophosphate (cGMP), which mediates many of the effects of NO. NO can also interact with molecular oxygen and superoxide anion to
produce reactive nitrogen species that can modify various cellular functions. These indirect effects of NO have a significant role in inflammation,
where NO is produced in high amounts by inducible nitric oxide synthase (iNOS) and reactive oxygen species are synthesized by activated
inflammatory cells. The present review deals with NO production and signaling in inflammation, especially in relation to human neutrophils and
eosinophils.

INTRODUCTION microbial products, such as lipopolysaccharide (LPS) and dsRNA or


proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis
Since its discovery in 1987 [1,2], nitric oxide (NO) has been a target factor- (TNF-) and interferon- (IFN-) induces the expression of
of intensive research and drug development. NO is a gaseous signaling iNOS gene in various inflammatory and tissue cells. Binding of calmodulin
molecule that regulates various physiological and pathophysiological to iNOS is tight even at low [Ca2+]i, and therefore, iNOS is also called as a
responses in the human body. These include circulation and blood calcium-independent NOS, and it can constantly produce high levels of
pressure, platelet function, host defense, and neurotransmission in central NO for prolonged periods [11,14,15].
nervous system and in peripheral nerves.
The role of NO in host defense and immune responses was started to REGULATION OF iNOS EXPRESSION
be understood at the second half of the 1980s. Stuehr and Marletta Although iNOS expression has been shown in various mouse and human
reported that mouse macrophages produce nitrite and nitrate in response to cells, there are marked cell type and species specific differences in the
bacterial lipopolysaccharide [3], and a compound with the reactivity of responsiveness of iNOS expression to different stimuli [14-16]. For
NO proved to be an intermediate in the process [4]. Hibbs and co-workers instance, responses in human cells seem to be quite different from those in
were able to identify NO as an effector molecule in macrophage- mouse cells, which have been widely used in the studies on iNOS
mediated cytotoxicity [5,6]. Since then, a number of reports on the effects expression. Many mouse cells readily express iNOS in response to LPS or
of NO in inflammatory responses have been published. High levels of NO to a single cytokine, whereas human cells usually require a combination of
are produced in response to inflammatory stimuli and mediate different cytokines for detectable iNOS expression and NO synthesis.
proinflammatory and destructive effects. However, like most other Furthermore, iNOS is expressed at high levels in activated murine
inflammatory mediators, NO has also protective effects in some macrophages, but it has been difficult to induce iNOS in human monocytes
inflammatory responses. / macrophages in vitro, although iNOS expression in macrophages in
The physiological and pathophysiological role of NO in the respiratory inflamed human tissues has been shown in ex vivo studies [17-19].
system has been reviewed recently [7,8]. NO acts as a neurotransmitter in
NANC nerves and regulates smooth muscle tone. NO is also involved in Regulation of Murine iNOS Transcription
the host defense in bronchial epithelium, and it acts as an inflammatory Transcription of mouse iNOS gene is regulated by ~1 kb promoter
mediator in pathological states. Inhaled NO may have clinical implications [20,21], which contains putative binding sites for a number of transcription
in certain conditions as a bronchodilator and vasodilator, and NOS factors. In vivo footprinting assay revealed LPS-induced binding to
inhibitors are believed to be of benefit in inflammatory lung diseases. In octamer (Oct), E-box, nuclear factor kappa B (NF-B) and interferon-
addition, exhaled NO can be measured as a marker of asthma and other stimulated response element (ISRE) sites [22].
inflammatory lung diseases. In the present review, we will discuss the
regulation of NO production in response to inflammatory stimuli as well as The mouse iNOS promoter contains two NF-B elements, which are
the targets of NO, especially in neutrophilic and eosinophilic inflammation. critical for iNOS expression as site directed mutagenesis of either of these
sites significantly reduces promoter activity, and chemical inhibitors of
BIOSYNTHESIS OF NO NF-B prevent iNOS expression and NO production [23-26].
NO is synthesized from L-arginine in a reaction catalyzed by a family IFN- is an efficient enhancer of iNOS expression in most cells. iNOS
of nitric oxide synthase (NOS) enzymes. Active NOS is a tetramer formed expression is seriously impaired in macrophages from mice deficient of
by two NOS proteins and two calmodulin molecules. Conversion of L- signal transducer and activator of transcription 1 (Stat1) [27], IFN
arginine to NO and L-citrulline requires also NADPH and O2 as co- regulatory factor-1 (IRF-1) [28] or IFN consensus sequence binding
substrates and (6R)-tetrahydrobiopterin (BH4 ), FAD, FMN and iron protein (ICSBP) [29], demonstrating the importance of IFN-responsive
protoporphyrin IX (haem) as co-factors [9-11]. transcription factors in iNOS expression. iNOS promoter contains a
functional GAS site which binds Stat1 [30], and an ISRE site which binds a
Three different NOS isoforms have been characterized. The neuronal complex of IRF-1 and ICSBP [31,32].
NOS (nNOS, NOS I) is predominantly expressed in neurons in brain and
peripheral nervous system [12]. Endothelial NOS (eNOS, NOS III) is Next to a proximal NF-B site is an Oct site, which is also required for
mainly expressed in endothelial cells [13]. Both nNOS and eNOS are iNOS promoter activity. Oct site binds members of the POU family of
constitutively expressed and are inactive in resting cells. Increase in free transcription factors (Oct-1, Brn-3a, Brn-3b) and high mobility group
intracellular calcium concentration ([Ca2+ ] i) stabilizes the binding of proteins (HMG-I(Y)) [33-37]. HMG-I(Y) alone cannot promote
calmodulin to eNOS and nNOS, and activates the enzyme to produce NO. transcription, but it augments and stabilizes the p50/p65 binding to NF-B
Stimuli that increase the [Ca2+ ]i (eg. acetylcholine in endothelial cells) site [35]. Additional transcription factors which have been shown to
trigger the production of NO, and when the [Ca2+ ] i decreases, the NO regulate mouse iNOS promoter activity include Epithelium-specific Ets
production ceases. That regulation makes NO production by constitutively (ESE-1) [38] and CAAT/enhancer binding protein beta (C/EBP) [39].
expressed NOSs transient and short lasting [9-11]. The role of activator protein 1 (AP-1) family of transcription factors in the
regulation of murine iNOS transcription is unclear. Existence of both
The third isoform of the NOS family is the inducible NOS (iNOS, NOS positive and negative regulatory AP-1 sites has been reported [40,41], but
II). No iNOS expression is found in most resting cells. Exposure to the composition of AP-1 which binds to these sites is not known. Over-
expression of c-fos, fosB and c-jun suppresses iNOS promoter activity
*Address correspondence to this author at the Immunopharmacology Research [41]. Stat3 [42], Elk-3 [43] and upstream stimulatory factors 1 and 2 (USF-
Group, Medical School, FIN-33014 University of Tampere, Finland; Fax: + 358 3 1 and USF-2) [44] have been shown to negatively regulate iNOS
3551 8082; E-mail: eeva.moilanen@uta.fi transcription.

1568-010X/05 $50.00+.00 2005 Bentham Science Publishers Ltd.


472 Current Drug Targets - Inflammation & Allergy, 2005, Vol. 4, No. 4 Korhonen et al.

Regulation of Human iNOS Transcription production is higher than the Km of L-arginine for iNOS. Reduction of
intracellular L-arginine concentrations by overexpression of arginase or
The promoter of the human iNOS gene is rather different from the depletion of extracellular L-arginine reduces iNOS mRNA translation due
murine iNOS promoter. Deletion analysis of the human iNOS 5flanking to inactivation of eukaryotic initiation factor2, an important factor in
region indicates presence of regulatory elements on the length of 16 kb initiation of translation [82,83].
[45]. There is conflicting evidence about the presence of regulatory
elements on the first 4.7 kb of the human promoter. In some studies, Signaling Pathways Regulating iNOS Expression
induction by cytokines was reported when promoter constructs containing
the first 3.2 kb [46] and 1 kb [47] were used. However, other reports Various signal transduction pathways have been suggested to regulate
observed only basal activity but no induction by cytokines with constructs iNOS expression. The importance of pathways leading to the activation of
containing first 1 - 4.7 kb of the promoter [45,48-51]. transcription factors NF-B and Stat1 have been discussed above. cAMP
activating compounds can both enhance [78,84-86] and inhibit [86,87]
Human iNOS promoter is activated by NF-B. A proximal NF-B site cytokine induced iNOS expression. Use of PKC activating phorbol esters
seems to be important in controlling transcription of human iNOS or PKC inhibitors have mainly suggested a positive role for PKC in
[50,52,53], although lack of functionality for this site has also been cytokine induced iNOS expression [88-90], but also a negative role has
reported [51]. Several other functional NF-B sites have been found been reported [91,92]. This may reflect the observations that different
further upstream of the promoter [53,54]. PKC isoforms may have opposite effects [88,89,93].
IFN- is an important cytokine for iNOS expression in human cells like Although iNOS activity is independent of the [Ca2+ ] i, changes in
in murine cells (see above). However, the IFN- -inducible factors that [Ca2+]i regulate iNOS expression. Both stimulation [94,95] and inhibition
regulate the activity of human iNOS promoter are less well-characterized [77,96]of iNOS expression by [Ca 2+ ] i elevating agents have been
than those that regulate the mouse promoter. Two functional GAS sites reported. Interestingly, the effect of [Ca2+]i seems to depend on the extent
have been found. The upstream site contains overlapping NF-B and Stat1 of inducing stimulus. At low LPS concentrations, increase in [Ca2+ ] i
binding sites, and binding of both of these factors to this site is required for stimulates iNOS expression, whereas at high LPS concentrations, increase
promoter activity [55]. in [Ca2+]i inhibits iNOS expression [97].
Additional factors shown to regulate human iNOS transcription The role of the mitogen-activated protein kinases in the regulation of
include C/EPB [56] and Krppel-like factor 6 (KLF6) [57]. Both positive iNOS expression has been investigated intensively. Extracellular signal-
and negative regulatory AP-1 sites have been found in the human iNOS regulated kinase 1 and 2 have been shown to up-regulate [98-101] or to
promoter [58-60], and the activity of the human promoter is suppressed by have no role [102,103] in iNOS expression. Also p38 MAP kinase has
overexpressing c-jun and c-fos [61]. Human iNOS promoter contains also been reported to up-regulate [101,104,105], down-regulate, [106-108] or
a negative regulatory element, which binds NF-B repressing factor, that to have no role [109,110] in iNOS expression. Activation of JNK up-
is a constitutively expressed silencer that acts as a suppressor of basal regulates iNOS expression [73,111,112].
transcription [62].
The inter-species differences in the promoters mostly explain the NO: MOLECULAR MECHANISMS OF ACTION
differences in the inducibility of iNOS expression between human and NO is a reactive molecule that has a variety of effects depending on
murine cells [48]. However, activation of NF-B and Stat1 pathways the relative concentrations of NO and the surrounding milieu in which NO
seems to be important for both human and mouse iNOS transcription. is produced. There are both direct effects of NO that are mediated by the
Post-Transcriptional Regulation of iNOS Expression NO molecule itself, and indirect effects of NO that are mediated by
reactive nitrogen species produced by the interaction of NO with
Recent evidence supports the idea that regulation of iNOS mRNA superoxide anion or with oxygen. cGMP that is produced by the interaction
stability is an important means to regulate iNOS expression. In of NO with soluble guanylate cyclase, mediates many of the physiological
unstimulated cells, nuclear run-on assays show continuous iNOS effects of NO, and it is also an important example of the direct effects of
transcription, and human iNOS promoter constructs have basal activity. NO.
However, no iNOS mRNA or protein can be detected in these cells, The molecular mechanisms that mediate the biological activities of
suggesting that the iNOS mRNA is highly unstable in unstimulated cells NO can be divided into three categories. Firstly, NO reacts readily with
[45,49,63]. The basal activity of the human iNOS promoter is suppressed, transition metals, such as iron, copper and zinc. These metals are
and its inducibility is increased if the luciferase construct also contains the abundantly present in prosthetic groups of enzymes and other proteins, and
3-untranslated region (UTR) of the human iNOS mRNA [64]. Both by that mechanism, NO regulates the activity of various enzymes.
human and murine 3-UTRs contain AU-rich elements (AREs) [65,66], Secondly, NO is able to induce the formation of S-nitrosothiols from
which are characterized by the presence of AUUUA pentamers or cysteine residues in a reaction called S-nitrosylation. Nitrosylation has
UUAUUUAUU nonamers. AREs have been shown to control mRNA been shown to modify the activity of several proteins involved in cellular
stability and translation of many transiently expressed cytokines and regulatory mechanisms [113]. Thirdly, NO reacts very quickly with
growth factors [67]. superoxide anion (O2-), resulting in the formation of peroxynitrite (ONOO -).
There is only fragmentary data on factors / mechanisms that regulate Peroxynitrite is a nitrating agent and a powerful oxidant that is able to
iNOS mRNA stability. Treatment with inhibitor of translation, modify proteins, lipids and nucleic acids.
cycloheximide, stabilizes mouse iNOS mRNA, suggesting that stability of The first mechanism represents direct effects of NO and the two latter
iNOS mRNA is regulated by factors, which require de novo protein mechanisms are referred as indirect effects of NO. At low concentrations
synthesis, or that the stability is coupled to translation [68-70]. It seems that of NO (< 1uM), the direct effects of NO predominate, whereas at higher
the 3-UTR ARE sequences of human iNOS mRNA alone are not concentrations (> 1uM), the indirect effects become more important [114]
sufficient for destabilization, but additional elements in the 3-UTR are (Fig. 1).
required [71]. 3-UTR of iNOS mRNA binds an mRNA stability regulating
protein HuR [71]. Down-regulation of HuR expression results in reduced NO Signaling through Transition Metals
iNOS expression and NO production without reduction in promoter
activity. This suggests that HuR stabilizes iNOS mRNA [71]. Due to its chemical structure, NO can act as an electron donor in
Protein kinase C (PKC ) [72] and c-Jun N-terminal kinase (JNK) [73] chemical reactions, and thereby is prone to react with transition metals
have been implicated in the regulation of iNOS mRNA stability. Reduced resulting in the formation of metal-nitrosyl complexes. In biological
iNOS mRNA stability has also been observed after treatment with systems, important transition metals that react with NO are iron, copper
transforming growth factor (TGF-) [74], dexamethasone [75], 8- and zinc.
bromo-cyclic guanosine monophosphate (cGMP) [76] and intracellular One of the main targets in NO signaling is soluble guanylate cyclase
calcium elevating agents [77]. Increased iNOS mRNA stability has been (sGC). sGC is an enzyme containing a heme structure with ferrous iron,
observed after treatment with forskolin (activates adenylate cyclase) or and it converts GTP to an important intracellular signaling molecule
dibutyryl cyclic adenosine monophosphate (cAMP) (membrane permeable cGMP. The basal activity of sGC is low, but it is rapidly activated by even
cAMP analog) [78,79], following BH4 [80] or the -adrenergic agonist, low concentrations of NO (10-100nM). NO binds directly to the heme in
isoproterenol [81]. sGS to form a ferrous-nitrosyl-heme complex resulting in changes in the
Interestingly, it was recently shown that in addition to serving as a porphyrin ring structure. This leads to the activation of sGC and 400-500-
substrate of NO biosynthesis, L-arginine also controls iNOS expression. fold increase in the rate of cGMP synthesis [114,115].
The intracellular L-arginine concentration required for maximal NO
Nitric Oxide Production and Signaling in Inflammation Current Drug Targets - Inflammation & Allergy, 2005, Vol. 4, No. 4 473

Fig. (1). NO production and targets of NO-mediated signaling. Activation of a cell surface receptor by its agonists, such as acetylcholine in endothelial cells or glutamate
in neurons, leads to an increase in the intracellular free calcium concentration ([Ca2+ ]i ) that subsequently results in the activation of NO production by eNOS or nNOS.
Inflammatory signals, such as bacterial products or proinflammatory cytokines, induce the expression of iNOS that is able to synthesize NO independently of changes in
[Ca2+]i. Effects of NO are mediated mainly via three routes. Firstly, NO can react directly with transition metals (e.g. iron, copper and zinc) found in catalytic sites in enzymes
like guanylate cyclase. This leads to formation of metal-nitrosyl complexes, and it may result in changes in the catalytic activity of the target enzyme. Secondly, NO can react
with cysteinyl residues of proteins forming nitrosothiols in a reaction called S-nitrosylation. S-nitrosylation may alter the activity of proteins in a similar manner as
phosphorylation, and it is a reversible event. Thirdly, a reaction between NO and superoxide anion results in a formation of peroxynitrite (ONOO-) that is a strong oxidant
and nitrating agent that is able to modify proteins, lipids and nucleic acids.

The principal mediator of cGMP signals is cGMP dependent protein decomposed rapidly to nitrosonium ion (NO+) and nitrite. Nitrosonium ion
kinase (PKG). PKG is a serine/threonine kinase that is activated upon is responsible for the nitrosylation of thiols, secondary amines and
binding of cGMP. Two types of PKG have been characterized. PKG I is a phenolics. Rate of autoxidation is mainly dependent on the concentrations
cytosolic enzyme that is ubiquitously expressed with particularly high of NO and oxygen, and it is dramatically accelerated within lipid
expression levels in cerebellum, platelets and smooth muscle cells. PKG I membranes. This means that the rate of formation of N2O 3 is high at the
has various targets which are related to smooth muscle relaxation and to site of NO synthesis. This stresses the importance of the distance between
platelet and neutrophil activation. [116,117]. PKG I deficient mice show the site of NO synthesis and target molecules and subcellular environment
vascular, intestinal and erectile dysfunction [118,119], which stresses the and conditions in NO signaling [113].
mediator role of cGMP and PKG I in the NO-induced smooth muscle Although nitrosylation of proteins is a chemical reaction, there seems
relaxation. PKG II is a membrane-bound protein that is expressed in to be specificity, which is a requirement for a proper signaling mechanism.
various tissues but not in the cardiovascular system. It is related to For example, p21 ras , a kinase involved in the MAP kinase cascade
intestinal secretory functions, and PKG II knockout resulted in intestinal activation, is a target for NO-based signaling. p21ras contains four cysteine
secretory defects and dwarfism [120]. residues, but only cysteine 118 is nitrosylated resulting in the activation
Other factors that convey cGMP mediated signaling are cyclic nucleotide [127]. Another example is coxsackievirus protease A2 that is inhibited by
gated channels (CNG), cAMP dependent protein kinase (PKA) and nitrosylation of cysteine 110 [128]. The group of cellular target proteins
phosphodiesterases. CNGs are voltage gated cation channels that are that are regulated by S-nitrosylation is increasing, and includes
involved in the processing of visual information in retina [121,122]. transcription factors, kinases involved in signaling cascades, caspases, ion
Because the cyclic nucleotide binding domains of PKG and PKA have channels and metabolic protein as shown in Table 1.
significant homology, cGMP is able to activate PKA, although with a 50-
fold lower selectivity than cAMP [116,117]. Fourth target of cGMP is NO Signaling through Peroxynitrite
phosphodiesterases (PDEs), which catalyze the conversion / inactivation Reaction between NO and superoxide anion (O2-) forms ONOO- that
of cAMP or cGMP to 5AMP and 5GMP, respectively. Different families is a reactive molecule able to nitrate and oxidize proteins, lipid, and
of PDEs are either regulated (stimulated or inhibited) by cGMP or they nucleotides. The reaction between NO and superoxide anion is very rapid,
target cGMP. PDE 5 is specific for cGMP, and selective inhibitors of this the rate constant of the reaction being about three times grater than the
enzyme are widely used in the treatment of erectile dysfunction. PDE 5 rate of superoxide decomposition by superoxide dismutase (SOD). The
inhibitors, such as sildenafil, enhance cGMP levels and by that mechanism, rate of ONOO- production is strongly dependent on the presence of NO
augment NO-induced vasodilatation in penile vessels [116,117,123]. and superoxide, and ONOO- formation is favored in an environment
Another well-documented target of direct NO regulated signaling is containing equivalent amounts of NO and superoxide. Sources of
cytochrome c oxidase (CcO). CcO is the terminal enzyme of the electron superoxide production are mainly considered to be mitochondria and
transport chain, which is responsible for the synthesis of ATP in immune cells (macrophages and granulocytes), and the synthesis of both
mitochondria. CcO contains two heme moieties and two Cu2+ centers. NO NO and superoxide is increased in inflammation [114].
has been found to inhibit CcO function in a reversible manner, thereby Excessive peroxynitrite formation leads to nitrated proteins, inhibition
hindering mitochondrial respiration [124,125]. Another example is of mitochondrial respiration, depletion of cellular energetics, DNA
catalase, which is a ferric heme containing protein responsible for the damage, apoptosis and necrotic cell death, resulting in cellular/tissue injury
metabolism of hydrogen peroxidase. NO reacts with the ferric moiety [114,129] (See Table 2). Nitrotyrosine has been used as a marker of
resulting in the inhibition of catalase function. This leads to the increased peroxynitrite formation and tissue injury. Tyrosine nitration is becoming
intracellular concentrations of hydrogen peroxide, and may contribute to increasingly recognized also as a functionally significant protein
the cytotoxicity of NO [126]. modification. Nitration of proteins and enzymes modulates catalytic
activity, cell signaling and cytoskeletal organization. [129-131]. It is of
NO Signaling through S-Nitrosylation
interest that also the activity of iNOS is regulated by ONOO- mediated
S-nitrosylation of proteins has been recognized as an important nitration. Nitration of iNOS decreases catalytic activity, and this may be a
mechanism that regulates the functions of the target proteins, and it has regulatory mechanism in patients with sepsis [132]. NO can also nitrate
been even compared to protein phosphorylation [113]. In aqueous tyrosine residues within proteins without formation of ONOO- . For
solutions, NO reacts readily with molecular oxygen (O2 ) forming example, NO has been shown to nitrate tyrosine residues and thereby
dinitrogen trioxide (N2O3) in a process called as NO autoxidation. N2O3 is
474 Current Drug Targets - Inflammation & Allergy, 2005, Vol. 4, No. 4 Korhonen et al.

Table 1. Modulation of Protein Functions by S-Nitrosylation

Protein Target Effect Ref.

Transcription factors
OxyR S-nitrosylation Cys199 or Cys208 activation [170]
SoxR nitrosylation of [2Fe-2S] clusters activation [171]
Ace-1 formation of S-nitrosothiols or disulfides inhibition [172]
NF-kB S-nitrosylation of p50 (Cys62) inhibition of DNA binding [151,152]
AP-1 S-nitrosylation of c-Jun Cys272 and c-Fos Cys54 inhibition of DNA binding [162,163]
S-glutathionylation Cys269
(DNA binding domain)
Kinases
ras
p21 S-nitrosylation of Cys118 activation [127,228]
JNK S-nitrosylation of Cys116 inhibition [229]
c-Src
p60 S-nitrosylation, S-S bond formation inhibition [230]
EGFR tyrosine kinase inhibition [231]
Caspases
Caspases 3 and 9 inhibition [232,233]
Ion channels
Ryanodine receptors S-nitrosylation of Cys3635 desensitization [234]
NMDA receptor S-nitrosylation of Cys399 inhibition [235]
Metabolic proteins
Creatine kinase inhibition [236]
Ornithine kinase inhibition [237]

inhibit activity of enzymes cyclooxygenase-1 [133] and cyclooxygenase-2 NO AND INFECTION CONTROL
[134].
Exposure of inflammatory and tissue cells to bacterial products such
NO AND REGULATION OF IMMUNE RESPONSE as LPS, lipoteichoic acid (LTA), peptidoglycan, or bacterial DNA, or to
intact bacteria, induces iNOS expression and enhanced NO production. In
The research that led to the discovery of NO as a signaling factor in these conditions, NO produced by iNOS, partly through formation of
biological systems was conducted largely in the field of cardiovascular peroxynitrite, is a cytotoxic molecule serving as a killing mechanism
research. Still, the connection between NO and immune system was against invading microbes [140-144]. The importance of iNOS expression
observed already in the early days of NO research, when NO was found and NO formation in the control of infectious agents is well-established in
to be the mediator of macrophage cytotoxicity [6]. Since then, the rodents. To date, data gathered from studies with iNOS gene-deficient
conception of the role of NO in immune system has broaden vastly. NO mice strongly suggest that NO has a central role in fighting viral, bacterial
has been found to be involved in a number of regulatory functions in and protozoa infections in mice [14,144].
inflammation. These include infection control, regulation of signaling
The role of iNOS expression in antimicrobial reactions in humans is
cascades and transcription factors, regulation of vascular responses, and
not as clear, and may be less important than in rodents. There is
regulation of leukocyte rolling, migration, cytokine production,
nonetheless evidence that iNOS expression also participates in anti-
proliferation and apoptosis [14,135-137]. Inhibitors of NO synthesis,
microbial defense in humans. Increased iNOS expression has been
especially selective iNOS inhibitors have been shown to be anti-
observed in patients with urinary tract infection, tuberculosis, malaria and
inflammatory in various forms of experimentally induced inflammation,
sepsis [141,145-147], and human neutrophils are found to produce NO-
such as arthritis and colitis [135,137-139], and selective iNOS inhibitors
derived oxidants through myeloperoxidase [148]. In addition, human
are under development for treatment of inflammatory diseases.

Table 2. Effects of Oxidation and Nitration Reactions Induced by Peroxynitrite

Protein Effect Ref.

Oxidation
DNA breakage, base modification, activation of PARP [238-240]
Thiols GSH oxidation [241]
Lipids peroxidation [242]
Mitochondrial enzymes inhibition-depletion in cellular energetics [243]
Nitration
Prostaglandin I2 synthase inhibition, reduction in PGI2 dependent vasorelaxation [244,245]
Manganese SOD inhibition, transplant rejection [246]
Cyclooxygenase 1 inhibition [133]
Cyclooxygenase 2 inhibition [134]
Ribonucleotide reductase inhibition [247]
Nitric Oxide Production and Signaling in Inflammation Current Drug Targets - Inflammation & Allergy, 2005, Vol. 4, No. 4 475

macrophages are found to induce iNOS expression and NO formation also neutrophils do not have the same action in human neutrophils, at least
in aseptic inflammation, e.g. in rheumatoid arthritis and aseptic loosening under in vitro conditions, and enzymatic production of NO in human
of joint implants [18,19]. In these conditions, the cytotoxic effects of NO neutrophils remains controversial. However, expression of iNOS is likely
that were originally aimed against invading microbes are focused against to occur in certain situations in vivo, because neutrophils isolated from the
host tissues and involved in the pathogenesis of inflammation and tissue oral cavity or from urine from patients with urinary track infections were
destruction. reported to express iNOS [146,175]. In addition, it was shown that
bacterial infection or treatment with cytokines resulted in iNOS expression
REGULATION OF INFLAMMATORY TRANSCRIPTION and nitration of ingested bacteria in human neutrophils [146,176]. In
FACTORS BY NO contrast, many researchers have not found NO synthesis in human
neutrophils [177-181]. We found that even though activated neutrophils
Cellular responses to oxidative and nitrosative stress are often
did not produce NO, they converted N-hydroxy-L-arginine to nitrite,
regulated at the level of transcription [149]. Both prokaryotic and
nitrate and citrulline [181]. Interestingly, enzyme myeloperoxide, which is
eukaryotic cells have transcription factors that are regulated by NO.
present in neutrophils, has been shown to produce nitrating oxidants and
B Pathway
NF- nitrotyrosine from hydrogen peroxide and nitrite [182].
In addition to direct antimicrobial effects, NO also regulates
The family of NF-B/Rel transcription factors has a central role in the
neutrophil functions. In in vitro studies, NO / NO-donors have been shown
regulation of inflammatory responses in mammalian cells including T and
to inhibit degranulation, leukotriene production, superoxide anion
B cell proliferation, expression of cytokines and adhesion molecules, as
generation and chemotactic movement in activated neutrophils [183,184].
well as regulation of apoptosis. NF-B activation is involved in several
NO has also shown to regulate leukocyte recruitment into the
pathological states in humans, such as asthma, rheumatoid arthritis, and
inflammatory focus. Endogenous NO as well as NO-releasing compounds
inflammatory bowel disease [150]. Activation of NF-B is essential for
attenuate leukocyte rolling and adhesion to activated endothelium [185-
iNOS expression (see above), and NO regulates NF-B at various points in
187]. The underlying mechanism is not known, but it has been related to
its activation cascade. NO has been shown to inhibit the activity of NF-B
antioxidant mechanisms of NO [188] and may be dependent on cGMP
by S-nitrosylation of p50 subunit [151,152]. In addition, NO has been
[187]. NO is also shown to down regulate adhesion molecules that mediate
found to positively modulate NF-B activation by affecting signaling
the interaction between leukocytes and endothelium, examples being P-
cascades regulating NF-B activation. One target is p21ras , which is
selectin [189], E-selectin [190] and intracellular adhesion molecule-1
activated by oxidative stress and leads to an increase in NF-B activity.
(ICAM-1) [185,191].
p21ras is activated by NO through S-nitrosylation of cysteine 118 residue
[127,153,154]. Dissociation of IB from NF-B leads to activation of NF- The role of NO on leukocyte recruitment in vivo is controversial.
B, and it is regulated by enzyme IKK. Transcription and degradation of Mice deficient in e N O S and n N O S were found to have enhanced
IKK has been reported to be modulated by NO resulting in reduced leukocyte migration in thioglycollate-induced peritonitis, while iNOS
activation of NF-B [155,156], whereas low concentrations of NO seem to deficient mice showed neutrophil infiltration comparable to that seen in
have an opposite effect [157]. In vivo studies show that NO up-regulates wild type mice [189]. iNOS knockout mice have been reported to have
NF-B activation in situations like hemorrhagic shock and reperfusion- markedly increased neutrophil activity and showed exacerbated
injury [158,159]. inflammation and tissue injury in experimental colitis [192,193]. In
contrast, selective inhibition of iNOS has been reported to reduce
AP-1 Pathway neutrophil infiltration and tissue injury in trinitrobenzene sulfonic acid
-induced colitis [194,195]. In addition to colitis, NO has been found to
AP-1 is a heterodimeric transcription factor consisting of c-fos and c-
regulate leukocyte accumulation in pathological states, such as allergic
jun subunits. NO regulates AP-1 activity in biological systems but the
lung inflammation [196,197], septic lung injury [198] and myocardial
effects seem to be cell type specific and concentration dependent. NO has
infarction [159].
been reported to up-regulate the expression of c-fos by a cGMP
-dependent mechanism [160,161]. NO was also found to enhance AP-1 NO AND EOSINOPHILS
dependent gene expression through activation of JNK [159]. In addition,
inhibition of AP-1 dependent transcription by S-nitrosylation of c-fos and The human bronchial epithelial lining expresses iNOS and produces
c-jun subunits has been reported [162,163]. NO [199], and endogenous NO can be detected in exhaled air [200,201].
The role of continuous NO production in lung epithelial cells is not clear,
Jak-STAT Pathway but it may be involved in maintaining mucosal defense mechanisms in
lungs. Patients with asthma show markedly elevated levels of NO in
The members of Janus family of tyrosine kinases (Jak1, Jak2, Jak3,
exhaled air [200,202,203], and they have enhanced iNOS expression and
Tyk2) are expressed ubiquitously, and are involved in the regulation of a
nitrated protein residues in airway epithelium and inflammatory cells [17].
number of cellular functions. They convey extracellular signals from
Exhaled NO levels correlate to clinical symptoms of asthma, to sputum
cellular surface to Stat proteins, which in turn activate transcriptional
eosinophilia, and to markers of eosinophil activation [203,208].
responses within the cell, leading to adaptation to altered extracellular
environment [164,165]. NO has been found to inhibit Jak2 and Jak3 NO production in human eosinophils is controversial. Arock et al.,
activities in kinase assays [166]. Accordingly, NO produced by activated reported that eosinophils produce NO when activated by IgE-
alveolar macrophages and myeloid suppressor cells inhibited T-cell immunocomplexes through CD23 receptors [209]. Purified eosinophils and
proliferation, and it was due to NO-dependent inhibition of Jak1 and Jak3 human eosinophilic leukemia cell line EOL-3 were found to produce NO
[167,168]. However, iNOS derived NO was found to enhance Stat3 and to express iNOS that was highly identical to macrophage iNOS [210].
dependent expression of IL-6 and G-CSF in mice suffering from However, there are also reports suggesting that eosinophils do not express
hemorrhagic shock [158]. iNOS [211,212]. Eosinophils may produce reactive nitrogen species also
by a NOS-independent manner through eosinophil peroxidase activity
Bacterial Transcription Factors [213,214].
OxyR is a bacterial transcriptional activator in E.coli that has been shown NO seems to regulate eosinophil accumulation into the site of allergic
to be activated by NO through S-nitrosylation of cysteine residues inflammation by its effects on adhesion molecules, migration and
[169,170]. Another bacterial activator of transcription, SoxR is activated apoptosis. NO and NO donors have been reported to inhibit eosinophil
by NO through nitrosylation of [2Fe-2S] clusters within the protein [171]. adhesion and migration in vitro [215-217]. However, in animal models of
The activation of these transcription factors leads to protective response to allergic airway inflammation, iNOS derived NO was associated with
nitrosative and oxidative conditions in bacteria. In yeast, activity of a accumulation of eosinophils and exacerbation of lung inflammation.
metal-responsive transcription factor Ace1 was found to be attenuated by Accordingly, iNOS deficient mice showed decreased eosinophil
NO, possibly through formation of S-nitrosothiols or disulfides [172]. accumulation in experimentally induced allergic lung inflammation. This
was associated with increased production of Th1 cytokine, IFN, and
NO AND NEUTROPHILS depletion of IFN led to enhanced eosinophil accumulation in lung tissue
and more severe inflammation [218,219]. Interestingly, iNOS knockout
There are interspecies differences in the synthesis of NO by
mice were more susceptible to pulmonary fibrosis than wild-type mice
neutrophils. Rodent neutrophils are known to produce NO through iNOS
[220]. This may, however, be rather due to altered neutrophil than
pathway in response to inflammatory stimuli, such as LPS, TNF- and
eosinophil functions or survival [221,222]. Interestingly, a recent report
IFN- [173,174]. Inflammatory stimuli known to induce iNOS in rat
showed that NO-releasing budesonide was more potent than budesonide in
476 Current Drug Targets - Inflammation & Allergy, 2005, Vol. 4, No. 4 Korhonen et al.

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C/EBP = CAAT/Enhancer binding protein [27] Meraz, M.A.; White, J.M.; Sheehan, K.C.; Bach, E.A.; Rodig, S.J.;
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