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• W2070299986 abstract "Nitrosative stress can occur when reactive nitric oxide (NO) species compromise the function of biomolecules via formation of NO adducts on critical amine and thiol residues. The capacity of inducible nitric-oxide synthase (iNOS) to generate nitrosative stress was investigated in the murine macrophage line ANA-1. Sequential activation with the cytokines IFN-γ and either tumor necrosis factor-α or interleukin-1β resulted in the induction of iNOS and production of nitrite (20 nm/min) but failed to elicit nitrosation of extracellular 2,3-diaminonapthalene. Stimulation with IFN-γ and bacterial lipopolysaccharide increased the relative level of iNOS protein and nitrite production of ANA-1 cells 2-fold; however, a substantial level of NO in the media was also observed, and nitrosation of 2,3-diaminonapthalene was increased greater than 30-fold. Selective scavenger compounds suggested that the salient nitrosating mechanism was the NO/O2 reaction leading to N2O3 formation. These data mimicked the pattern observed with a 5 μm concentration of the synthetic NO donor (Z)-1-[N-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NO). The NO profiles derived from iNOS can be distinct and depend on the inductive signal cascades. The diverse consequences of NO production in macrophages may reside in the cellular mechanisms that control the ability of iNOS to form N2O3 and elicit nitrosative stress. Nitrosative stress can occur when reactive nitric oxide (NO) species compromise the function of biomolecules via formation of NO adducts on critical amine and thiol residues. The capacity of inducible nitric-oxide synthase (iNOS) to generate nitrosative stress was investigated in the murine macrophage line ANA-1. Sequential activation with the cytokines IFN-γ and either tumor necrosis factor-α or interleukin-1β resulted in the induction of iNOS and production of nitrite (20 nm/min) but failed to elicit nitrosation of extracellular 2,3-diaminonapthalene. Stimulation with IFN-γ and bacterial lipopolysaccharide increased the relative level of iNOS protein and nitrite production of ANA-1 cells 2-fold; however, a substantial level of NO in the media was also observed, and nitrosation of 2,3-diaminonapthalene was increased greater than 30-fold. Selective scavenger compounds suggested that the salient nitrosating mechanism was the NO/O2 reaction leading to N2O3 formation. These data mimicked the pattern observed with a 5 μm concentration of the synthetic NO donor (Z)-1-[N-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NO). The NO profiles derived from iNOS can be distinct and depend on the inductive signal cascades. The diverse consequences of NO production in macrophages may reside in the cellular mechanisms that control the ability of iNOS to form N2O3 and elicit nitrosative stress. nitric oxide nitric-oxide synthase inducible NOS 2,3-diaminonapthalene interleukin lipopolysaccharide tumor necrosis factor (Z)-1-[N-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate Nitric oxide (NO)1 is a unique molecule that regulates numerous cellular functions solely through its chemical reactivity with the surrounding milieu. The formation of NO is catalyzed by a diverse family of nitric-oxide synthase (NOS) isoenzymes (1.Ignarro L.J. Buga G.M. Wood K.S. Byrns R.E. Chaudhuri G. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 9265-9269Crossref PubMed Scopus (4297) Google Scholar, 2.Bredt D.S. Synder S.H. Annu. Rev. Biochem. 1994; 63: 175-195Crossref PubMed Scopus (2127) Google Scholar, 3.Griffith O.W. Stuehr D.J. Annu. Rev. Physiol. 1995; 57: 707-736Crossref PubMed Google Scholar, 4.Geller D.A. Billiar T.R. Cancer Metastasis Rev. 1998; 17: 7-23Crossref PubMed Scopus (273) Google Scholar, 5.Geller D.A. Lowenstein C.J. Shapiro R.A. Nussler A.K. Di Silvio M. Wang S.C. Nakayama D.K. Simmons R.L. Snyder S.H. Billiar T.R. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3491-3495Crossref PubMed Scopus (807) Google Scholar, 6.MacMicking J. Xie Q-W. Nathan C. Annu. Rev. Immunol. 1997; 15: 323-350Crossref PubMed Scopus (3442) Google Scholar). Activation of the immune system can result in the expression of the inducible isoenzyme iNOS in numerous cell types (e.g. macrophages, neutrophils, glia, and hepatocytes). Although iNOS has been implicated in a diverse array of pathologic events, the relative contributions of NO and derived reactive nitrogen oxide species to disease processes are often unclear. Moreover, whether immune-stimulated cells can regulate the reactivity of NO per se by shifting the balance between NO and its various intermediate reaction partners, thereby altering subsequent effector interactions of nitrogen oxide species with target biomolecules, remains unanswered. In this study, we address these issues in the context of nitrosative stress, a condition often opposing oxidative stress (7.Grisham M.B. Jourd'Heuil D. Wink D.A. Am. J. Physiol. 1999; 276: G315-G321PubMed Google Scholar, 8.Wink D.A. Mitchell J.B. Free Radical Biol. Med. 1998; 25: 434-456Crossref PubMed Scopus (1296) Google Scholar, 9.Espey M.G. Miranda K.M. Feelisch M. Fukuto J. Grisham M.B. Vitek M.P. Wink D.A. Ann. N. Y. Acad. Sci. 2000; 899 (in press)PubMed Google Scholar), that may be a major factor in predicting the role iNOS plays during inflammation and disease.In nitrosation reactions, N-nitrosamines andS-nitrosothiols are formed by the addition of a nitrosonium equivalent (NO+) to amine and thiol moieties, respectively (10.Williams D.L.H. Nitrosation. Cambridge Press, Oxford, United Kingdom1988Google Scholar). Activation of rodent macrophages with both IFN-γ and LPS results in iNOS expression and nitrosation of target molecules present in the culture medium (11.Stuehr D.J. Marletta M.A. Proc. Natl. Acad. Sc. U. S. A. 1985; 82: 7738-7742Crossref PubMed Scopus (1008) Google Scholar, 12.Iyengar R. Stuehr D.J. Marletta M.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6369-6373Crossref PubMed Scopus (622) Google Scholar, 13.Miwa M. Stuehr D.J. Marletta M.A. Wishnok J.S. Tannenbaum S.R. Carcinogenesis. 1987; 8: 955-958Crossref PubMed Scopus (194) Google Scholar, 14.Kosaka H. Wishnok J.S. Miwa M. Leaf C.D. Tannenbaum S.R. Carcinogenesis. 1989; 10: 563-566Crossref PubMed Scopus (74) Google Scholar, 15.Simon D.I. Mullins M.E. Jia L. Gaston B. Singel D.J. Stamler J.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4736-4741Crossref PubMed Scopus (184) Google Scholar). Several iNOS-dependent reaction pathways have potential relevance in the nitrosation chemistry of biological systems. Acidified nitrite (HNO2) is a nitrosating agent, but it is formed only in low pH environments, such as that of the stomach (10.Williams D.L.H. Nitrosation. Cambridge Press, Oxford, United Kingdom1988Google Scholar, 15.Simon D.I. Mullins M.E. Jia L. Gaston B. Singel D.J. Stamler J.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4736-4741Crossref PubMed Scopus (184) Google Scholar). The mobilization of nonheme iron nitrosyl complexes from macrophages and hepatocytes activated with both cytokines and LPS (16.Lancaster Jr., J.R. Hibbs Jr., J.B. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1223-1227Crossref PubMed Scopus (487) Google Scholar, 17.Nüssler A.K. Geller D.A. Sweetland M.A. Di Silvio M. Billiar T.R. Madariaga J.B. Simmons R.L. Lancaster Jr., J.R. Biochem. Biophys. Res. Commun. 1993; 194: 826-835Crossref PubMed Scopus (87) Google Scholar) may provide a mechanism for nitrosation, in particular, trans-S-nitrosation (18.Boese M. Mordvintcev P.I. Vanin A.F. Busse R. Mülsch A. J. Biol. Chem. 1995; 270: 29244-29249Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Dinitrogen trioxide (N2O3) formed by the reaction of NO with molecular oxygen (O2) has a strong propensity to nitrosate both amine and thiol moieties at physiological pH (19.Wink D.A. Nims R.W. Darbyshire J.F. Christodoulou D. Hanbauer I. Cox G.W. Laval F. Laval J. Cook J.A. Krishna M.C. De Graff W.G. Mitchell J.B. Chem. Res. Toxicol. 1994; 7: 519-525Crossref PubMed Scopus (354) Google Scholar). The present study examined the nitrogen oxide profiles of a murine macrophage cell line to determine the conditions that may result in nitrosative stress on the extracellular milieu. The data show that macrophages produce a nitrosating agent consistent with the chemical profile of N2O3 (14.Kosaka H. Wishnok J.S. Miwa M. Leaf C.D. Tannenbaum S.R. Carcinogenesis. 1989; 10: 563-566Crossref PubMed Scopus (74) Google Scholar); however, this phenotype was dictated by the inductive stimuli received by the macrophage.DISCUSSIONSynthetic donors such as PAPA/NO can generate NO flux sufficient to elicit nitrosation reactions via N2O3. Of the NOS isozymes, only iNOS can catalyze the formation of similarly high levels of NO for prolonged periods of time. This is due, in part, to the continuous association of calmodulin with iNOS and a decreased susceptibility to product feedback inhibition. The present study showed that the capacity of cells to nitrosate extracellular target compounds was not due solely to the presence of iNOS but was also dependent on the nature of the inductive stimuli.Relationship between Nitrite, Nitrate, and NO Trapped by OxymyoglobinNitrite and nitrate are stable higher oxidation products of NO that are often used as indirect measurements of NOS activity in aerobic aqueous media (25.Ignarro L.J. Fukuto J.M. Griscavage J.M. Rogers N.E. Byrns R.E. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8103-8207Crossref PubMed Scopus (745) Google Scholar, 26.Lewis R.S. Tamir S. Tannenbaum S.R. Deen W.M. J. Biol. Chem. 1995; 270: 29350-29355Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Nitrite can be derived from numerous nitrogen oxide reactions. The stimulation of IFN-γ-primed ANA-1 cells with bacterial LPS resulted in the formation of approximately 2-fold more nitrite than that formed by cells stimulated with the cytokines IL-1β or TNF-α (Fig. 1 A). For each condition, nitrite values were highly correlated with the level of NO trapped by extracellular oxymyoglobin (Fig. 1 B); however, the rate of nitrite production was greater than that of oxymyoglobin oxidation. NO is trapped extremely rapidly by the dioxygen ferrous heme adduct of oxymyoglobin (k = 3.4 × 107m−1 s−1; Ref. 27.Eich R.F. Li T. Lemon D.D. Doherty D.H. Curry S.R. Aitken J.F. Mathews A.J. Johnson K.A. Smith R.D. Phillips Jr., G.N. Olson J.S. Biochemistry. 1996; 35: 6976-6983Crossref PubMed Scopus (564) Google Scholar). These data suggest that a portion of the NO derived from iNOS was oxidized to nitrite prior to leaving the cell and that this occurs regardless of the immunostimulant combinations used to induce iNOS expression.Nitrate is derived primarily from the interactions of NO with oxyhemoproteins. An apparent constitutive release of nitrate (2 nm/min) from unstimulated ANA-1 cells was observed. Substitution of l-arginine with the iNOS competitive inhibitor N-methylarginine, however, showed that this nitrate was not derived from endogenously produced NO. These data suggest that a modest portion of nitrate was taken up from the culture media via anion transporters and was subsequently released following incubation in nitrate-free buffer during the assay period (28.Shingles R. Roh M.H. McCarty R.E. J. Bioenerg. Biomembr. 1997; 29: 611-616Crossref PubMed Scopus (39) Google Scholar). A minor level of iNOS-specific nitrate (2 nm/min) production was distinguished from background only in cultures of ANA-1 cells stimulated with IFN-γ and LPS.iNOS Inductive Signals Confer High NO Level and Nitrosative CapacityThe concentration of NO derived from ANA-1 cells was measured either indirectly by oxymyoglobin oxidation or directly with an electrochemical probe. The oxymyoglobin data show that IFN-γ-primed ANA-1 cells produced incrementally greater amounts of NO following stimulation with either TNF-α, IL-1β, or LPS. In contrast, an electrochemical probe placed within 100 μm of the cell bed detected a substantial amount of NO in the assay buffer only with the IFN-γ/LPS stimulant combination (Fig. 2 A). Whereas oxymyoglobin can be envisioned as millions of randomly distributed highly sensitive NO probes, the electrochemical probe registers the presence of NO at a fixed and more distal point in space.The stark contrast in NO profiles with the electrochemical probe predicts that the nature of the NO interactions with molecular targets in the milieu surrounding a macrophage will differ dependent on the signals received for iNOS induction. This dichotomy was clearly illustrated in the capacity of murine macrophages to nitrosate the extracellular target compound DAN. Consistent with an earlier report using RAW 264.7 cells (15.Simon D.I. Mullins M.E. Jia L. Gaston B. Singel D.J. Stamler J.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4736-4741Crossref PubMed Scopus (184) Google Scholar), IFN-γ-primed ANA-1 cells stimulated with LPS nitrosated DAN present in the media. In comparison, the rate of DAN nitrosation in sister cultures of IFN-γ-primed ANA-1 cells stimulated with either TNF-α or IL-1β was 85–90% lower (Fig. 2 B). This dichotomy was also observed with primary murine macrophages, the IC-3, J774, and RAW 264.7 cell lines (data not shown). In addition, IFN-γ-primed macrophages nitrosated DAN following stimulation with LPS derived from Gram-positive bacteria as well as viral and parasite antigens (data not shown).Relationship of Nitrosative Capacity to iNOS Levels and Specific ActivityThe addition of superoxide dismutase, catalase, and urate to the assay buffer did not affect the levels of DAN nitrosation under each stimulant condition (Table I). These data suggested that the dichotomy for DAN nitrosation were not related to the differential consumption of NO by oxidative pathways. Rather, the mechanisms may operate at both the transcriptional and posttranslational levels. Western blot analysis showed that ANA-1 macrophages stimulated with IFN-γ and LPS had more than twice the iNOS protein of those treated with cytokines (Fig. 1 C). These data correspond to the differences observed for both nitrite production and oxymyoglobin oxidation. Nitrite production and nitrosative capacity were plotted as a function of cell density to examine whether nitrosative capacity was determined by the amount of iNOS per cell and the subsequent mass transport of NO. At an equivalence for nitrite production (and by extension, iNOS), the nitrosative capacity of ANA-1 cells stimulated with IFN-γ/LPS exceeded that of those stimulated with cytokines by 8–10-fold (Fig. 3). These data show that the specific activity of iNOS for nitrite formation and cellular nitrosative capacity are not coupled.Differences in nitrosative capacity may be related to the physical configuration of iNOS within the cell. Incubation of a sonication lysate derived from IFN-γ/LPS-stimulated ANA-1 cells in an optimized reaction mixture resulted in a 50% reduction in nitrite formation relative to that produced by intact cells. In contrast, lysis of ANA-1 cells stimulated with IFN-γ and TNF-α resulted in only a 10% reduction in nitrite formation. These data rule out the significance of arginine transport and the availability of iNOS co-factors (e.g. NADPH, tetrahydrobiopterin, and flavins) in conferring nitrosative capacity. Dilution of the cell contents upon lysis may alter the ratio between dimeric and inactive monomeric forms of iNOS in a manner independent of tetrahydrobiopterin levels (29.Baek K.J. Thiel B.A. Lucas S. Stuehr D.J. J. Biol. Chem. 1993; 268: 21120-21129Abstract Full Text PDF PubMed Google Scholar, 30.Ghosh D.K. Wu C. Pitters E. Moloney M. Werner E.R. Mayer B. Stuehr D.J. Biochemistry. 1997; 36: 10609-10619Crossref PubMed Scopus (152) Google Scholar). Alternatively, a disproportional decrease in nitrite production from lysed IFN-γ/LPS-stimulated ANA-1 cells may reflect the disruption of a membrane association critical for catalytic activity. Although metabolic incorporation of radiolabeled myristate, palmitate, and acetate onto iNOS was not observed in immunoprecipitates from IFN-γ-stimulated macrophages (31.Vodovotz Y. Russell D. Xie Q.W. Bogdan C. Nathan C. J. Immunol. 1995; 154: 2914-2925PubMed Google Scholar), the status of iNOS acylation or prenylation in macrophages further stimulated with either cytokines or LPS remains unclear.Characterization of the Nitrosating SpeciesSynthetic iron nitrosyl complexes can catalyze NO exchange reactions through what has been termed transnitrosation (18.Boese M. Mordvintcev P.I. Vanin A.F. Busse R. Mülsch A. J. Biol. Chem. 1995; 270: 29244-29249Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 32.Vanin A.F. Malenkova I.V. Serezhenkov V.A. Nitric Oxide. 1997; 1: 191-203Crossref PubMed Scopus (170) Google Scholar). The elegant work by Lancaster and co-workers (16.Lancaster Jr., J.R. Hibbs Jr., J.B. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1223-1227Crossref PubMed Scopus (487) Google Scholar, 17.Nüssler A.K. Geller D.A. Sweetland M.A. Di Silvio M. Billiar T.R. Madariaga J.B. Simmons R.L. Lancaster Jr., J.R. Biochem. Biophys. Res. Commun. 1993; 194: 826-835Crossref PubMed Scopus (87) Google Scholar) has shown that cells such as macrophages and hepatocytes form iron nitrosyl complexes following iNOS induction with cytokines and LPS. A potential role for iron nitrosyl complexes in the nitrosation of DAN, however, was not supported by several data. First, the addition of iron scavengers to the assay buffer did not impede DAN nitrosation by IFN-γ/LPS-stimulated ANA-1 cells (Table I). An interesting exception, albeit at high concentrations, was phenanthroline. Second, approximately 225 μm (70 ng/μl) of the prototypical iron nitrosyl (NO+ donor) compound sodium nitroprusside was required to match the rate of DAN nitrosation observed with 4 × 105 IFN-γ/LPS-stimulated ANA-1 cells (Fig. 5 A). S-Nitrosation of albumin by synthetic dinitrosyl iron complexes also required concentrations in the high micromolar range (18.Boese M. Mordvintcev P.I. Vanin A.F. Busse R. Mülsch A. J. Biol. Chem. 1995; 270: 29244-29249Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). A recent study found that the cumulative effect of IFN-γ/LPS treatment on J774 macrophages was to decrease iron uptake (to less than 2 pg per 4 × 105 cells) rather than increase iron release (33.Mulero V. Brock J.H. Blood. 1999; 94: 2383-2389Crossref PubMed Google Scholar). Taken together, these data suggest that the observed level of DAN nitrosation by ANA-1 cells in our 3-h assay period was not due to an iron nitrosyl complex mechanism.Nitrite production was correlated with the NO profiles observed using oxymyoglobin regardless of stimulant status. In contrast, triazole formation from DAN and electrochemical detection of NO were exclusive to macrophages induced with IFN-γ/LPS. An enhanced capacity for NO to travel from a source cell to a distal point alters the potential reactivity of NO at that point. Specifically, the formation of the nitrosating agent N2O3 may predominate under these conditions. N2O3 was not initially accepted as a relevant species in biological systems because the rate constant for the reaction between NO and O2 was considered to be too slow (k = 2 × 106m−2 s−1; Ref. 34.Wink D.A. Darbyshire J.F. Nims R.W. Saavedra J.E. Ford P.C. Chem. Res. Toxicol. 1993; 6: 23-27Crossref PubMed Scopus (478) Google Scholar) to compete with other potential pathways for NO consumption (e.g.hemeproteins and superoxide). However, the rate of the NO/O2 reaction has a second-order dependence on NO concentration, indicating that the formation of N2O3 can prevail when the flux of NO is high (34.Wink D.A. Darbyshire J.F. Nims R.W. Saavedra J.E. Ford P.C. Chem. Res. Toxicol. 1993; 6: 23-27Crossref PubMed Scopus (478) Google Scholar, 35.Fukuto J. Adv. Pharmacol. 1995; 34: 1-15Crossref PubMed Scopus (59) Google Scholar, 36.Lewis R.S. Dean W.M. Chem. Res. Toxicol. 1994; 7: 568-574Crossref PubMed Scopus (243) Google Scholar).The synthetic NO donor PAPA/NO generates N2O3in an aerobic environment. Formation of both nitrite and triazole by 4 × 105 ANA-1 cells stimulated with IFN-γ/LPS was equivalent to that generated by approximately 5 μmPAPA/NO (Fig. 4). For both ANA-1 cells and PAPA/NO under these conditions, the IC50 values for the N2O3 scavenger compounds ascorbic acid and glutathione were remarkably similar (Fig. 5). These data suggest that N2O3 derived from the NO/O2reaction was the nitrosating agent for DAN consistent with the previous findings of Tannenbaum and co-workers (14.Kosaka H. Wishnok J.S. Miwa M. Leaf C.D. Tannenbaum S.R. Carcinogenesis. 1989; 10: 563-566Crossref PubMed Scopus (74) Google Scholar). The partitioning of NO and O2 to the hydrophobic regions of membranes can greatly accelerate their reactivity with each other (37.Liu X. Miller M.J.S. Joshi M.S. Thomas D.D. Lancaster Jr., J.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2175-2179Crossref PubMed Scopus (526) Google Scholar). However, two observations suggest that N2O3 was formed outside the cell. First, the profiles for NO in the media using the electrochemical probe and the nitrosation of DAN are congruous. Second, the uptake mobilities of ascorbate and glutathione into the macrophage cytoplasm are very different (14.Kosaka H. Wishnok J.S. Miwa M. Leaf C.D. Tannenbaum S.R. Carcinogenesis. 1989; 10: 563-566Crossref PubMed Scopus (74) Google Scholar). However, the quenching profiles of both ascorbate and glutathione were similar between nitrosating cells and PAPA/NO in solution.ConclusionThis study shows that nitrosative alterations may occur to biomolecules containing either thiol or amino moieties in cells neighboring macrophages only if iNOS was induced in a selective manner (e.g. activation by direct contact with pathogens or their products). Nitrosative conditions generated by synthetic NO donors have been shown to inhibit the activity of enzymes involved in glycolysis (37.Liu X. Miller M.J.S. Joshi M.S. Thomas D.D. Lancaster Jr., J.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2175-2179Crossref PubMed Scopus (526) Google Scholar) and DNA repair (38.Molina y Vedia L. McDonald B. Reep B. Brune B. DiSilvio M. Billiar T.R. Lapetina E.G. J. Biol. Chem. 1992; 267: 24929-24932Abstract Full Text PDF PubMed Google Scholar, 39.Laval F. Wink D.A. Carcinogenesis. 1994; 15: 443-447Crossref PubMed Scopus (197) Google Scholar). The nitrosative capacity of 4 × 105 LPS-activated ANA-1 cells was equivalent to that of 5 μm PAPA/NO in a volume of 1 ml (Fig.4 B). In the much smaller dimensions of a biological compartment, macrophages may elicit nitrosative stress through N2O3-mediated reactions equivalent to higher concentrations of NO donor. We have observed that IFN-γ/LPS-stimulated macrophages can inactivate target enzymes in neighboring cells equivalent to that achieved with millimolar levels of synthetic NO donor. 2X. Zhou and M. G. Espey, unpublished observations. Despite many advances in our understanding of redox mechanisms, the role of nitrosative stress in disease processes is poorly understood. This study provides a novel framework for deciphering how macrophages may regulate the nitrogen oxide chemistry derived from iNOS during specific pathologic situations. The data show that macrophage exposure to inflammatory cytokines in the absence of direct contact with infectious agents or their products was insufficient to prompt a nitrosative profile. Determination of the mechanisms that govern the relationship between nitrosative and oxidative stress will unlock many fundamental aspects regarding how nitrogen oxides are involved in fighting pathogens (40.Wink D.A. Laval J. Carcinogenesis. 1994; 15: 2125-2129Crossref PubMed Scopus (160) Google Scholar), regulating cell-mediated immunity (41.Fang F.C. J. Clin. Invest. 1997; 99: 2818-2825Crossref PubMed Google Scholar, 42.Bingisser R.M. Tilbrook P.A. Holt P.G. Kees U.R. J. Immunol. 1998; 160: 5729-5734PubMed Google Scholar), and eliciting deleterious bystander effects on host tissue (7.Grisham M.B. Jourd'Heuil D. Wink D.A. Am. J. Physiol. 1999; 276: G315-G321PubMed Google Scholar, 8.Wink D.A. Mitchell J.B. Free Radical Biol. Med. 1998; 25: 434-456Crossref PubMed Scopus (1296) Google Scholar, 9.Espey M.G. Miranda K.M. Feelisch M. Fukuto J. Grisham M.B. Vitek M.P. Wink D.A. Ann. N. Y. Acad. Sci. 2000; 899 (in press)PubMed Google Scholar). Identification of genes and proteins that act as nitrosative switches may provide new pharmacological targets to control iNOS-generated nitrogen oxide chemistry in a wide range of diseases. Nitric oxide (NO)1 is a unique molecule that regulates numerous cellular functions solely through its chemical reactivity with the surrounding milieu. The formation of NO is catalyzed by a diverse family of nitric-oxide synthase (NOS) isoenzymes (1.Ignarro L.J. Buga G.M. Wood K.S. Byrns R.E. Chaudhuri G. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 9265-9269Crossref PubMed Scopus (4297) Google Scholar, 2.Bredt D.S. Synder S.H. Annu. Rev. Biochem. 1994; 63: 175-195Crossref PubMed Scopus (2127) Google Scholar, 3.Griffith O.W. Stuehr D.J. Annu. Rev. Physiol. 1995; 57: 707-736Crossref PubMed Google Scholar, 4.Geller D.A. Billiar T.R. Cancer Metastasis Rev. 1998; 17: 7-23Crossref PubMed Scopus (273) Google Scholar, 5.Geller D.A. Lowenstein C.J. Shapiro R.A. Nussler A.K. Di Silvio M. Wang S.C. Nakayama D.K. Simmons R.L. Snyder S.H. Billiar T.R. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3491-3495Crossref PubMed Scopus (807) Google Scholar, 6.MacMicking J. Xie Q-W. Nathan C. Annu. Rev. Immunol. 1997; 15: 323-350Crossref PubMed Scopus (3442) Google Scholar). Activation of the immune system can result in the expression of the inducible isoenzyme iNOS in numerous cell types (e.g. macrophages, neutrophils, glia, and hepatocytes). Although iNOS has been implicated in a diverse array of pathologic events, the relative contributions of NO and derived reactive nitrogen oxide species to disease processes are often unclear. Moreover, whether immune-stimulated cells can regulate the reactivity of NO per se by shifting the balance between NO and its various intermediate reaction partners, thereby altering subsequent effector interactions of nitrogen oxide species with target biomolecules, remains unanswered. In this study, we address these issues in the context of nitrosative stress, a condition often opposing oxidative stress (7.Grisham M.B. Jourd'Heuil D. Wink D.A. Am. J. Physiol. 1999; 276: G315-G321PubMed Google Scholar, 8.Wink D.A. Mitchell J.B. Free Radical Biol. Med. 1998; 25: 434-456Crossref PubMed Scopus (1296) Google Scholar, 9.Espey M.G. Miranda K.M. Feelisch M. Fukuto J. Grisham M.B. Vitek M.P. Wink D.A. Ann. N. Y. Acad. Sci. 2000; 899 (in press)PubMed Google Scholar), that may be a major factor in predicting the role iNOS plays during inflammation and disease. In nitrosation reactions, N-nitrosamines andS-nitrosothiols are formed by the addition of a nitrosonium equivalent (NO+) to amine and thiol moieties, respectively (10.Williams D.L.H. Nitrosation. Cambridge Press, Oxford, United Kingdom1988Google Scholar). Activation of rodent macrophages with both IFN-γ and LPS results in iNOS expression and nitrosation of target molecules present in the culture medium (11.Stuehr D.J. Marletta M.A. Proc. Natl. Acad. Sc. U. S. A. 1985; 82: 7738-7742Crossref PubMed Scopus (1008) Google Scholar, 12.Iyengar R. Stuehr D.J. Marletta M.A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6369-6373Crossref PubMed Scopus (622) Google Scholar, 13.Miwa M. Stuehr D.J. Marletta M.A. Wishnok J.S. Tannenbaum S.R. Carcinogenesis. 1987; 8: 955-958Crossref PubMed Scopus (194) Google Scholar, 14.Kosaka H. Wishnok J.S. Miwa M. Leaf C.D. Tannenbaum S.R. Carcinogenesis. 1989; 10: 563-566Crossref PubMed Scopus (74) Google Scholar, 15.Simon D.I. Mullins M.E. Jia L. Gaston B. Singel D.J. Stamler J.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4736-4741Crossref PubMed Scopus (184) Google Scholar). Several iNOS-dependent reaction pathways have potential relevance in the nitrosation chemistry of biological systems. Acidified nitrite (HNO2) is a nitrosating agent, but it is formed only in low pH environments, such as that of the stomach (10.Williams D.L.H. Nitrosation. Cambridge Press, Oxford, United Kingdom1988Google Scholar, 15.Simon D.I. Mullins M.E. Jia L. Gaston B. Singel D.J. Stamler J.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4736-4741Crossref PubMed Scopus (184) Google Scholar). The mobilization of nonheme iron nitrosyl complexes from macrophages and hepatocytes activated with both cytokines and LPS (16.Lancaster Jr., J.R. Hibbs Jr., J.B. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1223-1227Crossref PubMed Scopus (487) Google Scholar, 17.Nüssler A.K. Geller D.A. Sweetland M.A. Di Silvio M. Billiar T.R. Madariaga J.B. Simmons R.L. Lancaster Jr., J.R. 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The data show that macrophages produce a nitrosating agent consistent with the chemical profile of N2O3 (14.Kosaka H. Wishnok" @default.
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