By
From the Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, D-91054 Erlangen, Germany
Study of the role of nitric oxide (NO) in mammalian organisms has a history of complexities. When eukaryotic
cells were demonstrated to generate NO from the aminoacid L-arginine, we were first stunned and then fascinated by the idea that a molecule with such a simple structure exerts messenger functions and regulates complex life processes. Soon, however, we had to learn that there are at
least three different isoforms of nitric oxide synthases (NOS),
which all catalyze the same redox reaction, but differ in
biochemical and structural properties, output of NO, function, distribution, and regulation (1, 2). The introduction
of the acronyms ncNOS, iNOS, and ecNOS helped us to
memorize that the type 1 NOS is constitutively expressed
in neurons, where its activity is regulated by Ca2+ gradients
and is critical for neurotransmission and learning; that the
type 2 NOS is transcriptionally induced by cytokines, is independent of elevations of calcium, and is prototypically expressed in inflammatory macrophages, which makes them
cytotoxic against microbial pathogens and tumor cells; and
that the type 3 isoform is found as a constitutive enzyme in
the endothelial layer of blood vessels, thereby regulating
vascular tone and adhesion of circulating blood cells. Of
course, it was not long before this simplified conception of
a benign and host-protective NO world was challenged by
the discovery of harmful effects of NO such as neurotoxicity, reperfusion injury, and severe hypotension during endotoxic shock (1, 2).
For immunologists in particular, iNOS turned out to be
both friend and foe: on the one hand iNOS-derived NO
conveys protection against many (but by no means all) intracellular bacteria and parasites, helps to fight several viral
infections, and is implicated in the control of malignancies
(3). On the other hand iNOS might also promote tumor
angiogenesis and metastasis (7, 8), and (i)NOS-dependent
tissue destruction and/or disease has been seen in several
rodent autoimmunity models, such as experimental allergic
encephalitis (EAE) and uveitis (EAU), inflammatory arthritis, and immune complex glomerulonephritis (9). Now, a
number of recent studies, published in this and other journals, again extend our ideas of NO function in (auto)immunity and infectious diseases, as highlighted below.
A frequently proposed cascade for the development of organ-specific autoimmune disease invokes the induction and expansion of Th1 in response to microbial antigens and IL-12, which secrete interferon IFN- However, the picture on the role of iNOS/NO in rodent EAE is far from uniform. The results obtained by
Fenyk-Melody et al. (18) are in accordance with three
studies in the rat EAE model, but at first glance contradict
another set of studies with different strains of mice, in
which treatment with aminoguanidine (an NOS inhibitor
with relative selectivity for iNOS), D609 (an inhibitor of
activity of phosphatidylcholine-specific phospholipase C), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO; an NO scavenger), or uric acid (a putative scavenger of peroxinitrite) ameliorated the severity of
EAE. The results of these studies are summarized in Table
1, and as recently proposed by Gold et al. (25), are best reconciled by the assumption that iNOS can exhibit two different roles in EAE, either of which might prevail depending on the mode of induction: when EAE is induced by
the injection of MBP-specific T cells (adoptive transfer
model), the production of NO triggered by the encephalitogenic T cells appears to be primarily tissue-damaging,
whereas in EAE directly induced by immunization with
MBP the main function of NO appears to be counterregulatory and disease-limiting. There is certainly an impact of
the species (rat versus mouse) and the mouse strain as illustrated by the disparate results obtained by Brenner et al.
(13). As to the findings of Hooper et al. (26) (Table 1), it is
important to bear in mind that phosphatidylcholine-phospholipase C is the key enzyme of a signaling pathway that
has many intracellular targets with no specificity for the induction of iNOS. The potent protective effect of uric acid
clearly deserves further clarification, especially because the
NO levels in the brains of mice treated with uric acid were
prominently increased rather than decreased (26). In view
of the discrepancies between the studies listed in Table 1, it
would be wise to avoid the use of NOS inhibitors, which
are already known to suppress general stimulatory pathways (e.g., D609), exhibit functions unrelated to NOS (e.g.,
aminoguanidine, which inhibits copper-containing amine
oxidases, catalase, and the formation of advanced glycosylation end-products, and generates hydrogen peroxide in the
presence of Cu2+; 27 and references therein) or show little
or no selectivity for the inducible isoform of NOS (e.g.,
the L-arginine analogues L-NAME and L-NMMA, which
impair iNOS, ncNOS, and ecNOS activity and cause hypertension and loss of weight; 28, 29, and references therein). As a final point, iNOS-positive cells in the CNS
from diseased SJL mice (or in the brain from multiple sclerosis patients) have been identified as members of the macrophage/microglia as well as astrocyte lineages (26, 30), but
it remains speculative to ascribe the opposing functions of
NO to these different cell types.
Table 1
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References
and
thereby activate macrophages and other effector cells for
the production of tissue-damaging molecules such as reactive oxygen intermediates or NO. Several parts of this concept have been repeatedly challenged, particularly in the
EAE mouse model, which shares some similarities with human multiple sclerosis. In mice in which EAE was induced
via immunization with myelin basic protein (MBP) combined with microbial adjuvants, it has been uniformly
shown that IFN-
is not only dispensible for the development of encephalitis, but clearly protects against disease progression or relapses in susceptible mice and contributes
to the resistance of strains in which EAE cannot be elicited
(15, 16). Segal et al. recently reported in this journal that
the induction of EAE in IFN-
/
mice can be prevented
by the simultaneous administration of anti-IL-12 antibodies and that IL-12
/
mice are completely resistant to disease development, most likely due to the expansion of a
MBP nonspecific CD4+ T cell population that produces
IL-10, counterregulates the encephalitogenic (EAE effector) T cells, and is itself subjected to control by IL-12.
Lymph node cells from anti-IL-12-treated and immunized mice were unable to transfer the disease to naive recipients, and splenocytes from naive donors treated with anti-IL-12
suppressed the development of EAE in immunized recipients (17). The above findings argue for a disease-protective
role of IFN-
and a disease-promoting function of endogenous IL-12 that becomes overt in the absence of endogenous IFN-
. In both cases the cytokine effect might be mediated by iNOS-derived NO. Segal et al. observed high
levels of TNF-
and iNOS mRNA in the spinal cords of
MBP-immunized C57BL/6 IFN-
/
mice, which were
markedly reduced after treatment with anti-IL-12 (17).
This is compatible with but certainly does not prove the idea that iNOS/NO contributes to the IFN-
-independent disease-promoting effect of IL-12. In contrast, in
IFN-
+/+ PL/J mice, the pharmacologic inhibition or genetic deletion of iNOS was associated with an increased incidence and/or enhanced severity of EAE induced by immunization with MBP (18). Comparable results were also
obtained by Kahl et al. (19). This strongly suggests a protective, antiinflammatory role of iNOS. Possible underlying mechanisms include known functions of iNOS/NO
such as the suppression of T cell proliferation and Th1 cytokine production, the reduction of leukocyte adhesion
and infiltration, the inhibition of other tissue-damaging
pathways (e.g., NADPH oxidase), the scavenging of superoxide, and/or the apoptosis of macrophages or (encephalitogenic) T cells (for review see references 5 and 20; 21-24).
Effect of (i)NOS inhibition on the course of EAE*
Protective and disease-mediating roles of iNOS/NO
have also been discovered in two other autoimmune disease models, supporting the existence of a general principle. In the rat model of autoimmune interstitial nephritis,
treatment with L-N6-(1-iminoethyl)-lysine (L-NIL), a potent and relatively selective inhibitor of iNOS, intensified
the renal injury (29). In EAU induced by immunization
with interphotoreceptor retinoid binding protein in adjuvants, genetic deletion of iNOS or low-dose (50 mg/kg)
treatment with L-NAME delayed the onset and decreased
the severity of the ocular inflammation, whereas high-dose
treatment with L-NAME was previously seen to exacerbate the disease (14 and references therein; 31). These findings point to a proinflammatory effect of iNOS in EAU
and illustrate the difficulty of interpreting results obtained
with the nonselective NOS inhibitor L-NAME. Similar to
the EAE model, EAU will develop in the absence of endogenous IFN-, and endogenous IFN-
at the systemic
level appears to play a disease-limiting, protective role
(31a). Whether this latter effect also involves iNOS remains
to be investigated.
iNOS/NO does not have universal antimicrobial potency.
First, several microbial species (e.g., Salmonella, Mycobaterium avium/intracellulare, Mycobacterium tuberculosis) exhibit
intrinsic or strain-dependent resistance to NO, the molecular basis of which has begun to be unravelled. Second, in a
number of infections (e.g., M. avium infections, influenza
virus pneumonia, rabies, or borna virus encephalitis) expression of iNOS was clearly correlated with disease progression, arguing for a proinflammatory, autotoxic, and/or immunosuppressive function of NO (for review see references
2, 4, 6). So far, iNOS appeared to be either protective or counterprotective for the course and outcome of a given
infectious disease. A clear exception to this rule has now
been demonstrated by Khan et al. in the C57BL/6 mouse
model of Toxoplasma gondii infection (34). After low dose
infection (20 cysts), 50% of iNOS+/+ mice survived beyond
day 90, whereas all iNOS/
mice had died by day 30, which is in agreement with the results from previous studies (35 and references therein). In contrast, when the parasite
inoculum was increased to 50-100 cysts, all iNOS+/+ mice
died within 12 d, but most of the iNOS
/
mice survived
for
21 d. Histology revealed extensive fatty degeneration
of the liver and necrosis of the distal ileum in iNOS+/+
mice, whereas both organs were intact in iNOS
/
or aminoguanidine-treated wild-type mice. However, the numbers of parasites in the brain and liver of iNOS
/
mice were
3- or 15-fold higher compared to wild-type controls. Thus,
iNOS appears to account for the tissue damage seen in the gut and liver, but simultaneously confers some protection
against the parasites in the liver and the brain. As intestinal
necrosis in T. gondii-infected wild-type mice can also be
prevented by anti-IFN-
treatment (36), the prominent
induction of iNOS in the small bowel is likely to be due to
the hyperexpression of IFN-
.
There is considerable evidence from in vitro experiments that iNOS-derived NO can modulate the cytokine response of macrophages, T cells, endothelial cells, and fibroblasts. This might be due to its capacity to activate and inactivate ion channels, G proteins, protein tyrosine kinases, Janus kinases, redox sensitive kinases, and transcription factors (for review see references 37, 38). Two recent studies highlight the possibility that NO assumes a similar regulatory function also in vivo.
Hierholzer et al. (39) analyzed the function of iNOS in a
murine model of hemorrhagic shock. They report that the
deletion of the iNOS gene in the mouse or pharmacologic
inhibition of iNOS by L-NIL in the rat reduced the degree
of tissue injury in liver and lung, which in control animals
occurred within 4 h of resuscitation. The authors further
demonstrate that in the absence of iNOS the activation of
two transcription factors (NF-B and Stat3) was significantly reduced in the lung and liver. The same was true for
the expression of IL-6 and G-CSF, which are critical components of the inflammatory response following resuscitation from shock and are thought to be controlled by NF-
B
and Stat3. Although the stimulus for the induction of
iNOS in this model remains to be elucidated, the data support the conclusion that iNOS serves both tissue-damaging
and cytokine regulatory functions in this model.
In the mouse model of cutaneous leishmaniosis, iNOS
was previously identified as a critical antileishmanial mechanism which was thought to start operating only when
macrophages become activated by IFN--secreting CD4+
T cells (for review see references 4, 6). A recent study now
shows that the expression of iNOS is not restricted to the T-cell-dependent late phase of infection, but is also an important component of the innate response of the host,
where it is focally induced by IFN-
/
within the first 24 h
of infection (40). In iNOS
/
or L-NIL-treated wild-type
mice, there is a 30-fold reduction of the baseline expression
of IL-12 p40 mRNA, an almost complete lack of the upregulation of IFN-
, markedly reduced cytotoxic activity
of NK cells, and an upregulation of the macrophage-inhibitory cytokine TGF-
in the Leishmania major-infected skin
and/or lymph node. Furthermore, in the absence of iNOS
activity the parasites will disseminate (from the skin and
lymph node to the spleen, liver, bone marrow, and lung),
which is secondary to the lack of IFN-
. In vitro, lymph
node cells from day 1-infected mice fail to respond to IL-12
in the absence of iNOS (Diefenbach, A., M. Röllinghoff,
and C. Bogdan, manuscript in preparation), and macrophages from iNOS
/
mice are refractory to the downregulation of TGF-
1 production by IFN-
. Thus, the earlier
recognized antileishmanial activity of iNOS during the late
phase of infection now contrasts with a regulatory function
of NO during the innate response to L. major, the potential
sequence of which is summarized in Fig. 1.
|
The role of iNOS/NO in the immune system comprises both regulatory and effector functions. This first category includes immunosuppressive effects (e.g., inhibition of lymphocyte proliferation) and the modulation of the cytokine response. The second category includes immunopathologic effects (e.g., tissue destruction) and immunoprotective activities (e.g., killing of microbial pathogens or apoptosis of autoreactive T cells). The results discussed above illustrate that NO functions are not mutually exclusive. In fact, the prevailing data strongly suggest that signaling and effector functions of NO can operate in vivo in parallel, in a synergistic or antagonistic manner. Clearly, the mere detection of iNOS expression correlating directly or inversely with a clinical phenotype no longer allows us to draw firm conclusions as to its function. This makes it difficult to predict the effect of NO donors and iNOS inhibitors in a given disease. On the other hand, it is exactly this complexity that should encourage further studies on the pro- and antiinflammatory effects of NO, its cellular and tissue distribution, and the relationship between NO function and concentration in the microenvironment of inflammatory lesions. In this context it is also time to analyze the role of the neuronal and endothelial isoform of NOS in the immune system. No, there is no end yet to NO in immunology.
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Footnotes |
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Address correspondence to Christian Bogdan, Institut für klinische Mikrobiologie, Immunologie, und Hygiene, Friedrich-Alexander-Universität Erlangen-Nürnberg, Wasserturmstrasse 3, D-91054 Erlangen, Germany. Phone: 011-49-9131-852647; Fax: 011-49-9131-852573; E-mail: christian.bogdan{at}mikrobio.med.uni-erlangen.de
Received for publication 24 February 1998.
I thank Drs. A. Diefenbach, C. Nathan, M. Röllinghoff, and S. Stenger for their helpful comments and apologize to those authors whose work I could not cite directly due to the limits of space. ![]() |
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