Immunologic Research

, Volume 22, Issue 2–3, pp 319–341 | Cite as

Nitric oxide synthase 2 and cyclooxygenase 2 interactions in inflammation

  • J. Brice Weinberg


Nitric oxide (NO) and prostaglandin (PG) E2 produced by NO synthase type 2 (NOS2) and cyclooxygenase type 2 (COX2), respectively, are important mediators in inflammation. There is much information regarding their roles in models of inflammation in mice and in humans with diseases such as rheumatoid arthritis (RA). A variety of stimuli including cytokines, microbial components, immune complexes, and mechanical stress can induce both NOS2 and COX2 mRNA transcription and protein synthesis and enhance inflammation. This has been demonstrated in both mice and humans. NOS2-specific inhibitors reduce inflammation in mice, and COX2-specific inhibitors reduce inflammation in mice and in humans. There is significant cross-talk between PGE2/NO and COX2/NOS2. Treatments that inhibit both NOS2 and COX2 should provide the most potent antiinflammatory effects.

Key Words

Nitric oxide Prostaglandin Monocyte macrophage inflammation rheumatoid arthritis 


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  1. 1.
    Cush JJ, Lipsky PE: Cellular basis for rheumatoid inflammation. Clin Ortho Rel Res 1991;265:9–22.Google Scholar
  2. 2.
    Harris ED, Jr: Rheumatoid arthritis. Pathophysiology and implications for therapy. New Eng J Med 1990;322:1277–1289.PubMedGoogle Scholar
  3. 3.
    Weyard CM, Goronzy JJ: Pathogenesis of rheumatoid arthritis. Adv Rheumatol 1997;81:29–55.Google Scholar
  4. 4.
    Brennan FM, Feldmann M: Cytokines in autoimmunity. Curr Opin Immunol 1992;4:754–759.PubMedGoogle Scholar
  5. 5.
    Alvaro-Gracia JM, Zvaifler NJ, Brown CB, Kaushansky K, Firestein GS: Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. J Immunol 1991;146: 3365–3371.PubMedGoogle Scholar
  6. 6.
    Talal N: Interleukins, interferon and rheumatic disease. Clin Rheum Dis 1985;11:633–644.PubMedGoogle Scholar
  7. 7.
    Hooks JJ, Jordan GW, Cupps T, Moutsopoulos HM, Fauci AS, Notkins AL: Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis. Arthritis Rheum 1982; 25:396–400.PubMedGoogle Scholar
  8. 8.
    Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Eng J Med 1993;329:2002–2012.Google Scholar
  9. 9.
    Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J 1992;6:3051–3064.PubMedGoogle Scholar
  10. 10.
    Beckman JS, Crow JP: Pathological implications of nitric oxide, superoxide and peroxynitrite formation. [Review]. Biochem Soc Trans 1993;21:330–334.PubMedGoogle Scholar
  11. 11.
    Magrinat G, Mason SN, Shami PJ, Weinberg JB: Nitric oxide modulation of human leukemia cell differentiation and gene expression. Blood 1992;80:1880–1884.PubMedGoogle Scholar
  12. 12.
    Punjabi CJ, Laskin DL, Heck DE, Laskin JD: Production of nitric oxide by murine bone marrow cells. Inverse correlation with cellular proliferation. J Immunol 1992;149:2179.PubMedGoogle Scholar
  13. 13.
    Stamler JS, Singel DJ, Loscalzo J: Biochemistry of nitric oxide and its redox-activated forms. [Review]. Science 1992;258:1898–1902.PubMedGoogle Scholar
  14. 14.
    Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT: Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun 1993;193: 398–405.PubMedGoogle Scholar
  15. 15.
    Charles IG, Palmer RMJ, Hickery MS, et al.: Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc Natl Acad Sci USA 1993;90:11,419–11,423.Google Scholar
  16. 16.
    Reiling N, Kroncke R, Ulmer AJ, Gendes J, Flad HD, Hauschildt S: Nitric oxide synthase—Expression of the endothelial, Ca2+/calmodulin-dependent in human B and T lymphocytes. Eur J Immunol 1996;26:511–516.PubMedGoogle Scholar
  17. 17.
    Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS: Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 1994;79:1137–1146.PubMedGoogle Scholar
  18. 18.
    Zhao HX, Dugas N, Mathiot C, et al.: B-cell chronic lymphocytic leukemia cells express a functional inducible nitric oxide synthase displaying anti-apoptotic activity. Blood 1998;92:1031–1043.PubMedGoogle Scholar
  19. 19.
    Stefanovic-Racic M, Stadler J, Georgescu HI, Evans CH: Nitric oxide synthesis and its regulation by rabbit synoviocytes. J Rheumatol 1994;21:1892–1898.PubMedGoogle Scholar
  20. 20.
    Nathan C, Xie Q-W: Regulation of biosynthesis of nitric oxide. J Biol Chem 1994;269:13,725–13,728.Google Scholar
  21. 21.
    Spitsin SV, Koprowski H, Michaels FH: Characterization and functional analysis of the human inducible nitric oxide synthase gene promoter. Molec Med 1996;2:226–235.Google Scholar
  22. 22.
    Devera ME, Shapiro RA, Nussler AK, et al.: Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines—initial analysis of the human NOS2 promoter. Proc Natl Acad Sci USA 1996;93: 1054–1059.Google Scholar
  23. 23.
    Taylor BS, Devera ME, Ganster RW, et al.: Multiple NF-kappa-B enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem 1998;273: 15,148–15,156.Google Scholar
  24. 24.
    Chartrain NA, Geller DA, Koty PP, et al.: Molecular cloning structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem 1994;269:6765–6772.PubMedGoogle Scholar
  25. 25.
    Kleinert H, Wallerath T, Fritz G, et al.: Cytokine induction of NO synthase II in human DLD-1 cells: roles of the JAK-STAT, AP-1 and NF-kappaB-signaling pathways. Brit J Pharmacol 1998;125: 193–201.Google Scholar
  26. 26.
    Kamijo R, Harada H, Matsuyama T, et al.: Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 1994;263:1612–1615.PubMedGoogle Scholar
  27. 27.
    Gao JJ, Filla MB, Fultz MJ, Vogel SN, Russell SW, Murphy WJ: Autocrine/paracrine IFN-alpha/beta mediates the lipopolysaccharide-induced activation of transcription factor Statlalpha in mouse macrophages: pivotal role of Statlalpha in induction of the inducible nitric oxide synthase gene. J Immunol 1998;161: 4803–4810.PubMedGoogle Scholar
  28. 28.
    Rodriguez-Pascual F, Hausding M, Ihrig-Biedert I, et al.: Complex contribution of the 3′-untranslated region to the expressional regulation of the human inducible nitric-oxide synthase gene—involvement of the RNA-binding protein HuR. J Biol Chem 2000;275:26,040–26,049.Google Scholar
  29. 29.
    Gross SS, Levi R: Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem 1992;267:25,722–25,729.Google Scholar
  30. 30.
    Assreuy J, Cunha FQ, Liew FY, Moncada S: Feedback inhibition of nitric oxide synthase activity by nitric oxide. Brit J Pharmacol 1993;108:833–837.Google Scholar
  31. 31.
    Rogers NE, Ignarro LJ: Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine. Biochem Biophys Res Commun 1992;189:242.PubMedGoogle Scholar
  32. 32.
    Denis M: Human monocytes/macrophages: NO or no NO? J Leukoc Biol 1994;55:682–684.PubMedGoogle Scholar
  33. 33.
    Weinberg JB, Misukonis MA, Shami PJ, et al.: Human mononuclear phagocyte inducible nitric oxide synthase (iNOS). Analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 1995;86:1184–1195.PubMedGoogle Scholar
  34. 34.
    Weinberg JB: Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review. Molecular Med 1998;4:577–591.Google Scholar
  35. 35.
    Appleton I, Tomlinson A, Willoughby DA: Induction of cyclo-oxygenase and nitric oxide synthase in inflammation. Adv Pharmacol 1996;35:27–78.PubMedGoogle Scholar
  36. 36.
    Smith WL, Garavito RM, DeWitt DL: Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and-2. J Biol Chem 1996;271: 33157–33,160.PubMedGoogle Scholar
  37. 37.
    Gilroy DW, Colville-Nash PR: New insights into the role of COX 2 in inflammation. J Molec Med 2000;78:121–129.Google Scholar
  38. 38.
    Langenbach R, Loftin C, Lee C, Tiano H: Cyclooxygenase knockout mice—models for elucidating isoform-specific functions [Review]. Biochem Pharmacol. 1999;58:1237–1246.PubMedGoogle Scholar
  39. 39.
    Blanco JCG, Contursi C, Salkowski CA, DeWitt DL, Ozato K, Vogel SN: Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression. J Exp Med 2000;191:2131–2144.PubMedGoogle Scholar
  40. 40.
    Wadleigh DJ, Reddy ST, Kopp E, Ghosh S, Herschman HR: Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J Biol Chem 2000; 275:6259–6266.PubMedGoogle Scholar
  41. 41.
    Harris ED, Jr. Text book of rheumatology, fourth ed. Philadelphia: W.B. Saunders Company; 1993.Google Scholar
  42. 42.
    Gaillard T, Mulsch A, Klein H, Decker K: Regulation by prostaglandin E2 of cytokine-elicited nitric oxide synthesis in rat liver macrophages. Biol Chem Hoppe Seyler 1992;373:897–902.PubMedGoogle Scholar
  43. 43.
    Marotta P, Sautebin L, Di Rosa M: Modulation of the induction of nitric oxide synthase by eicosanoids in the murine macrophage cell line J774. Brit J Pharmacol 1992; 107:640–641.Google Scholar
  44. 44.
    Imai Y, Kolb H, Burkart V: Nitric oxide production from macrophages is regulated by arachidonic acid metabolites. Biochem Biophys Res Commun 1993;197: 105–109.PubMedGoogle Scholar
  45. 45.
    Tetsuka T, Daphna-Iken D, Srivastava SK, Baier LD, DuMaine J, Morrison AR: Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1. Proc Natl Acad Sci USA 1994;91: 12,168–12,172.Google Scholar
  46. 46.
    Milano S, Arcoleo F, Dieli M, et al.: Prostaglandin E2 regulates inducible nitric oxide synthase in the murine macrophage cell line J774. Prostaglandins 1995;49: 105–115.PubMedGoogle Scholar
  47. 47.
    Stadler J, Harbrecht BG, Di Silvio M, et al. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol 1993;53:165–172.PubMedGoogle Scholar
  48. 48.
    Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 1993;90: 7240–7244.PubMedGoogle Scholar
  49. 49.
    Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR: Co-induction of nitric oxide synthase and cyclo-oxygenase: interactions between nitric oxide and prostanoids. Brit J Pharmacol 1995;114:1335–1342.Google Scholar
  50. 50.
    Vane JR, Mitchell JA, Appleton I, et al.: Inducible isoforms of cyclo-oxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci USA 1994;91:2046–2050.PubMedGoogle Scholar
  51. 51.
    Salvemini D, Manning PT, Zweifel BS, et al.: Dual inhibition of nitric oxide and prostaglandin production contributes to the anti-inflammatory properties of nitric oxide synthase inhibitors J Clin Invest 1995;96:301–308.PubMedGoogle Scholar
  52. 52.
    Amin AR, Vyas P, Attur M, et al.: The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc Natl Acad Sci USA 1995;92:7926–7930.PubMedGoogle Scholar
  53. 53.
    Pang L, Hoult JR: Repression of inducible nitric oxide synthase and cyclooxygenase-2 by prostaglandin E2 and other cyclic AMP stimulants in J774 macrophages [published erratum appears in Biochem Pharmacol 1997;53(12): 1945]. Biochem Pharmacol 1997; 53:493–500.PubMedGoogle Scholar
  54. 54.
    Stadler J, Stefanovic-Racic M, Billiar TR, et al.: Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J Immunol 1991; 147:3915–3920.PubMedGoogle Scholar
  55. 55.
    Salvemini D, Masferrer JL: Interactions of nitric oxide with cyclooxygenase: in vitro, ex vivo, and in vivo studies. Meth Enz 1996; 269:12–25.Google Scholar
  56. 56.
    Salvemini D, Manning PT, Zweifel BS, et al.: Dual inhibition of nitric oxide and prostaglandin production contributes to the antiinflammatory properties of nitric oxide synthase inhibitors. J Clin Invest 1995;96:301–308.PubMedGoogle Scholar
  57. 57.
    Sautebin L, Talenti A, Ianaro A, Di Rosa M: Modulation by nitric oxide of prostaglandin biosynthesis in the rat. Brit J Pharmacol 1995;114:323–328.Google Scholar
  58. 58.
    Lianos EA, Guglielmi K, Sharma M: Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury. Kidney Internat 1998;53:645–653.Google Scholar
  59. 59.
    Franchi AM, Chaud M, Rettori V, Suburo A, McCann SM, Gimeno M: Role of nitric oxide in eicosanoid synthesis and uterine motility in estrogen-treated rat uteri. Proc Natl Acad Sci USA 1994;91: 539–543.PubMedGoogle Scholar
  60. 60.
    Watkins DN, Garlepp MJ, Thompson PJ: Regulation of the inducible cyclo-oxygenase pathway in human cultured airway epithelial (A549) cells by nitric oxde. Brit J Pharmacol 1997;121:1482–1488.Google Scholar
  61. 61.
    Davidge ST, Baker PN, Laughlin MK, Roberts JM: Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. Circulation Res 1995;77:274–283.PubMedGoogle Scholar
  62. 62.
    Curtis JF, Reddy NG, Mason RP, Kalyanaraman B, Eling TE: Nitric oxide: a prost aglandin H synthase 1 and 2 reducing cosubstrate that does not stimulate cyclooxygenase activity or prostaglandin H synthase expression in murine macrophages. Arch Biochem Biophys 1996;335:369–376.PubMedGoogle Scholar
  63. 63.
    Clancy R, Varenika B, Huang WQ, et al.: Nitric oxide synthase/COX cross-talk: Nitric oxide activates COX-1 but inhibits COX-2-derived prostagladnin production. J Immunol 2000;165:1582–1587.PubMedGoogle Scholar
  64. 64.
    Marnett LJ, Wright TL, Crews BC, Tannenbaum SR, Marrow JD: Regulation of prostaglandin biosynthesis by nitric oxide is revealed by targeted deletion of inducible nitric-oxide synthase. J Biol Chem 2000;275:13,427–13,430.Google Scholar
  65. 65.
    Tsai AL, Wei C, Kulmacz RJ: Interaction between nitric oxide and prostaglandin H synthase. Arch Biochem Biophys 1994;313: 367–372.PubMedGoogle Scholar
  66. 66.
    Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P: The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990;265:16,737–16,740.Google Scholar
  67. 67.
    Zhang Y, DeWitt DL, McNeely TB, Wahl SM, Wahl LM: Secretory leukocyte protease inhibitor suppresses the production of monocyte prostaglandin H synthase-2, prostaglandin E2, and matrix metallo proteinases. J Clin Invest 1997;99:894–900.PubMedGoogle Scholar
  68. 68.
    Fujii I, Shingu M, Nobunaga M: Monocyte activation in early onset the umatoid arthritis. Ann Rheum Dis 1990;49:497–503.PubMedGoogle Scholar
  69. 69.
    Ricote M, Huang JT, Welch JS, Glass CK: The peroxisome proliferator-activated receptor gamma (PPAK gamma) as a regulator of monocyte/macrophage function. J Leuk Biol 1999;66: 733–739.Google Scholar
  70. 70.
    Mangelsdorf DJ, Evans RM: The RXR heterodimers and orphan receptors. Cell 1995;83: 841–850.PubMedGoogle Scholar
  71. 71.
    Serhan CN: Inflammation Signalling the fat controller. Nature 1996;384:23–24.PubMedGoogle Scholar
  72. 72.
    Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W: The PPAR alpha-leukotriene B4 pathway to inflammation control. Nature 1996;384:39–43.PubMedGoogle Scholar
  73. 73.
    Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK: The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391:79–82.PubMedGoogle Scholar
  74. 74.
    Jiang CY, Ting AT, Seed B: PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391: 82–86.PubMedGoogle Scholar
  75. 75.
    Ricote M, Huang J, Faijas L, et al.: Expression of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 1998;95:7614–7619.PubMedGoogle Scholar
  76. 76.
    Forman BM, Chen J, Evans RM: Hypolipidemic drugs polyumsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997;94:4312–4317.PubMedGoogle Scholar
  77. 77.
    Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997;272: 3406–3410.PubMedGoogle Scholar
  78. 78.
    Huang JT, Welch JS, Ricote M, et al.: Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 1999;400: 378–382.PubMedGoogle Scholar
  79. 79.
    Mbalaviele G, Abu-Amer Y, Meng A, et al.: Activation of peroxisome proliferator-activated receptor-gamma pathway inhibits osteoclast differentiation. J Biol Chem 2000; 275:14,388–14,393.Google Scholar
  80. 80.
    Weinberg JB, Granger DL, Pisetsky DS, et al.: The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increassed nitric oxide production and nitric oxide synthase expression in MRL-1pr/1pr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. J Exp Med 1994;179:651–660.PubMedGoogle Scholar
  81. 81.
    Reilly CM, Oates JC, Cook JA, Morrow JD, Halushka PV, Gilkeson GS: Inhibition of mesangial cell nitric oxide in MRL/lpr mice by prostaglandin J(2) and proliferator activation receptor-gamma agonists. J Immunol 2000;164: 1498–1504.PubMedGoogle Scholar
  82. 82.
    Colville-Nash PR, Qureshi SS, Willis D, Willoughby DA: Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxy genase 1. J Immunol 1998;161:978–984.PubMedGoogle Scholar
  83. 83.
    Inoue H, Tanabe T, Umesono K: Feedback control of cyclooxygenase-2 expression through PPAR gamma. J Biol Chem 2000;275: 28,028–28,032.Google Scholar
  84. 84.
    Chinetti G, Griglio S, Antonucci M, et al: Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 1998;273: 25,573–25,580.Google Scholar
  85. 85.
    Straus DS, Pascural G, Li M, et al.: 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibits multiple steps in the NF-kapa B signaling pathway. Proc Natl Acad Sci USA 2000;97:4844–4849.PubMedGoogle Scholar
  86. 86.
    Kawahito Y, Kondo M, Tsubouchi Y, et al.: 15-Deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 2000;106:189–197.PubMedGoogle Scholar
  87. 87.
    Clancy RM, Abramson SB: Nitric oxide—a novel mediator of inflammation [Review]. Proc Soc Exp Biol Med 1995;210:93–101.PubMedGoogle Scholar
  88. 88.
    Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS: Nitric oxide produced by human B lymphocytes inhibits apoptos is and Epstein-Barr virus reactivation. Cell 1994;79:1137–1146.PubMedGoogle Scholar
  89. 89.
    Evans CH, Stefanovic-Racic M, Lancaster JR, Jr.: Nitric oxide and its role in orthopaedic disease [Review]. Clin Ortho Rel Res 1995;312:275–294.Google Scholar
  90. 90.
    Darius H, Grodzinska L, Meyer J: The effects of the nitric oxide donors molsido mine and SIN-1 on human polymorphonuclear le ucocyte function in vitro and ex vivo. Eur J Clin Pharmacol 1992;43: 629–633.PubMedGoogle Scholar
  91. 91.
    Kubes P, Suzuki M, Granger DN: Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88: 4651–4655.PubMedGoogle Scholar
  92. 92.
    Stamler JS, Loscalzo J: The antiplatelet effects of organic nitrates and related nitroso compounds in vitro and in vivo and their relevance to cardiovascular disorders [see comments]. J Am Coll Card 1991;18:1529–1536.Google Scholar
  93. 93.
    Albina JE, Henry WL: Suppression of lymphocyte proliferation through the nitric oxide synthesizing pathway. J Surg Res 1991; 50:403–409.PubMedGoogle Scholar
  94. 94.
    Maciejewski JP, Selleri C, Sato T, et al.: Nitric oxide suppression of human hematopoiesis in vitro— contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest 1995;96:1085–1092.PubMedGoogle Scholar
  95. 95.
    Shami PJ, Weinberg JB: Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34(+) human bone marrow cells. Blood 1996;87: 977–982.PubMedGoogle Scholar
  96. 96.
    Weiss G, Goossen B, Doppler W, et al.: Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J 1993;12:3651–3657.PubMedGoogle Scholar
  97. 97.
    Drapier JC, Hirling H, Wietzerbin J, Kaldy P, Kuhn LC: Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J 1993;12:3643–3649.PubMedGoogle Scholar
  98. 98.
    Stefanovic-Racic M, Stadler J, Evans CH: Nitric oxide and arthritis. Arthritis Rheum 1993;36: 1036–1044.PubMedGoogle Scholar
  99. 99.
    Weinberg JB: Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/lpr mice. In Oxygen/nitrogen radicals and cellular injury, Adler KB (ed.). New York, Marcel Dekker, 1998.Google Scholar
  100. 100.
    Tamir S, Derojaswalker T, Gal A, et al.: Nitric oxide production in relation to spontaneous B-cell lymphoma and myositis in SJL mice. Cancer Res 1996;55:4391–4397.Google Scholar
  101. 101.
    Vodovotz Y, Geiser AG, Chesler L, et al.: Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta-1 null mouse. J Exp Med 1996;183: 2337–2342.PubMedGoogle Scholar
  102. 102.
    Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C: Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med 1993;178:605–613.PubMedGoogle Scholar
  103. 103.
    Farrell AJ, Blake DR, Palmer RM, Moncada S: Increased concentrations of nitrite in synovial fluidand serum samples suggest increased nitric oxide synthesis in the umatic diseases. Ann Rheum Dis 1992;51: 1219–1222.PubMedGoogle Scholar
  104. 104.
    Stichtenoth DO, Fauler J, Zeidler H, Frolich JC: Urinary nitrate excretion, is increased in patients with rheumatoid arthritis and reduced by prednisolone. Ann Rheum Dis 1995;54:820–824.PubMedGoogle Scholar
  105. 105.
    Grabowski PS, England AJ, Dykhuizen R, et al.: Elevated nitric oxide production in rheumatoid arthritis—detection using the fasting urinary nitrate/creatinine ratio. Arth Rheum 1996;39:643–647.Google Scholar
  106. 106.
    Kaur H, Halliwell B: Evidence for nitric oxide-mediated oxidative damage inchronic inflammation— nitrotyrosine inserum and synovial fluid from rheumatoid patients. FEBS Lett 1994;350:9–12.PubMedGoogle Scholar
  107. 107.
    Sakurai H, Kohsaka H, Liu MF, et al.: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 1995;96: 2357–2363.PubMedGoogle Scholar
  108. 108.
    McInnes LB, Leung BP, Field M, et al.: Production of nitric oxide in the synovial membrane of rheumatoid and os teoarthritis patients. J Exp Med 1996;184:1519–1524.PubMedGoogle Scholar
  109. 109.
    Ueki Y, Miyake S, Tominaga Y, Eguchi K: Increased nitric oxide levels in patients with rheumatoid arthritis. J Rheumatol 1996;23: 230–236.PubMedGoogle Scholar
  110. 110.
    St. Clair EW, Wilkinson WE, Lang T, et al.: Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients. J Exp Med 1996;184:1173–1178.PubMedGoogle Scholar
  111. 111.
    Griffiths RJ. Prostaglandins and inflammation. In Inflammation. Basic principles and clinical correlates, Gallin Ji, Snyderman R, (eds.), Philadelphia, PA: Lippincott Williams & Wilkins, 1999; 349–360.Google Scholar
  112. 112.
    Iniguez MA, Punzon C, Fresno M: Induction of cyclooxygenase-2 onactivated T lymphocytes: Regulation of T cell activation by cyclooxygenase-2 inhibitors. J Immunol 1999;163:111–119.PubMedGoogle Scholar
  113. 113.
    Garrone P, Galibert L, Rousset F, Fu SM, Banchereau J: Regulatory effects of prostaglandin E2 on the growth and differentiation of human B lymphocytes activated through their CD40 antigen. J Immunol 1994;152:4282–4290.PubMedGoogle Scholar
  114. 114.
    Roper RL, Phipps RP: Prostaglandin E2 and cAMP inhibit B lymphocyte activation and simultaneously promote IgE and 1gG1 synthesis. J Immunol 1992;149:2984–2991.PubMedGoogle Scholar
  115. 115.
    Cohen PL, Eisenberg RA: Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol 1991;9:243–269.PubMedGoogle Scholar
  116. 116.
    Nagata S, Suda T: Fas and Fas ligand: Ipr and gld mutations. Immunol Today 1995;16:39–43.PubMedGoogle Scholar
  117. 117.
    Dang-Vu AP, Pisetsky DS, Weinberg JB: Functional alterations of marcophages in autoimmune MRL-lpr/lpr mice. J Immunol 1987;138:1757–1761.PubMedGoogle Scholar
  118. 118.
    Spurney RF, Fan PY, Ruiz P, Sanfilippo F, Pisetsky DS, Coffman TM: Thromobxanerceptor blockade reduces renal injury in murine lupus nephritis. Kidney Internat 1992;41:973–982.Google Scholar
  119. 119.
    Fisher GH, Rosenberg FJ, Straus SE, et al.: Dominantinterfering Fas gene mutations impair apoptosis in a human auto immune lymphoproliferative syndrome. Cell 1995;81:935–946.PubMedGoogle Scholar
  120. 220.
    Henry Y, Lepoivre M, Drapier JC, Ducrocq C, Boucher JL, Guissani A: EPR characterization of molecular targets for NO in mammalian cells and organelles. FASEB J 1993;7:1124–1134.PubMedGoogle Scholar
  121. 121.
    Weinberg JB, Gilkeson GS, Mason RP, Chamulitrat W: Nitrosylation of blood hemoglobin and renal nonheme proteins in autoimmune MRL-lpr/lprmice. Free Radic Biol Med 1998;24:191–196.PubMedGoogle Scholar
  122. 122.
    Keng T, Privalle CT, Gilkeson GS, Weinberg JB: Peroxynitrite and decreased catalase in autoimmune mice. Mole cular Med 2000;6:779–792.Google Scholar
  123. 123.
    Beckman JS, Ye YZ, Anderson PG, Chen J, Accayitti MA, Tarpey MM, White CR: Extensive nitration of protein tyrosines in human a the rosclerosis detected by immunohisto chemistry. Biol Chem Hoppe-Seyler 1994;375:81–88.Google Scholar
  124. 124.
    Kooy NW, Royall JA, Ye YZ, Kelly DR, Beckman JS: Evidence for in vivo peroxynitrite production in human acute lung injury. Am J Respir Crit Care Med 1995;151:1250–1254.PubMedGoogle Scholar
  125. 125.
    Haddad IY, Pataki G, Hu P, Galliani C, Beckman JS, Matalon S: Quantitation of nitro tyrosinelevels in lungsections of patients andanimals with acute lung injury. J Clin Invest 1994;94:2407–2413.PubMedGoogle Scholar
  126. 126.
    Venkatraman JT, Chandrasekar B, Kim JD, Fernandes G: Genotype effects on the antioxidant enzymes activity and mRNA expression in liver and kidney tissues of autoimmune-prone MRL/MpJ-lpr/lpr mice. Biochim Biophys Acta 1994;1213:167–175.PubMedGoogle Scholar
  127. 127.
    Hang L, Theofilopoulos AN, Dixon FJ: A spontaneous rheumatoid arthritis-like disease in MRL-l mice. J Exp Med 1982; 155:1690–1701.PubMedGoogle Scholar
  128. 128.
    Eisenberg RA, Craven SY, Fisher CL, et al.: The genetics of autoantibody production in MRL/lpr lupus mice. Clin Exp Rheumatol 1989;7:S35-S40.PubMedGoogle Scholar
  129. 129.
    Gilkeson GS, Mudgett JS, Seldin MF, et al.: Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2. J Exp Med 1997;186:365–173.PubMedGoogle Scholar
  130. 130.
    Takahashi S, Nose M, Sasaki J, Yamamoto T, Kyogoku M: IgG3 production in MRL/lpr mice is responsible for development of lupus nephritis. J Immunol 1991; 147:515–519.PubMedGoogle Scholar
  131. 131.
    Steinman L: Some misconceptiors about unders tanding autoimmunity through experiments with knockouts. J Exp Med 1997;185:2039–2041.PubMedGoogle Scholar
  132. 132.
    Mori L, Iselin S, De Libero G, Lesslauer W: Attenuation of collagen-induced arthritis in 55-kDa TNF receptor typel (TNFRl)-IgGl-treatedant TNFRI-deficient mice. J Immunol 1996;157:3178–3182.PubMedGoogle Scholar
  133. 133.
    Piguet PF, Grau GE, Vesin C, Loetscher H, Gentz R, Lesslauer W: Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 1992;77:510–514.PubMedGoogle Scholar
  134. 134.
    Harriman G, Harper LK, Schaible TF: Summary of clinical trials in rheumatoid arthritis using infliximab, ananti-TNFalpha treatment. Ann Rheum Dis 1999;58:61–64.Google Scholar
  135. 135.
    Genaro AM, Hortelano S, Alvarez A, Martinez C, Bosca L: Splenic B lymphocyte programmed cell death is prevented by nitric oxide release through mechanisms involving sustained Bcl-2 levels. J Clin Invest 1995;95:1884–1890.PubMedGoogle Scholar
  136. 136.
    Lander HM, Ogiste JS, Pearce SFA, Levi R, Novogrodsky A: Nitric oxide-stimulated guanine nucleotide exchange on p21 (Ras). J Biol Chem 1995;270:7017–7020.PubMedGoogle Scholar
  137. 137.
    Schini VB, Durante W, Elizondo E, et al.: The induction of nitric oxide synthase activity is inhibited by TGF-β1, PDGF-AB and PDGF-BB invascular smooth muscle cells. Eur J Pharmacol 1992;216:379–383.PubMedGoogle Scholar
  138. 138.
    Fang FC: Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest 1997;100:S43-S50.Google Scholar
  139. 139.
    Clark IA, Rockett KA, Cowden, WB: Proposed link between cytokines, nitric oxide, and human cerebral malaria. Parasitol Today 1991;7:205–207.PubMedGoogle Scholar
  140. 140.
    Anstey NM, Weinberg JB, Hassanali M, et al.: Nitricoxide in Tanzanian children with malaria. Inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med 1996;184:557–567.PubMedGoogle Scholar
  141. 141.
    Anstey NM, Weinberg JB, Wang ZQ, Mwaikambo ED, Duffy PE, Granger DL: Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children. Am J Trop Med Hyg 1999;61:253–258.PubMedGoogle Scholar
  142. 142.
    Anstey NM, Granger DL, Hassanali MY, Mwaikambo ED, Duffy PE, Weinberg JB: Nitric oxide, malaria, and anemia: Inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children. Am J Trop Med Hyg 1999;61:249–252.PubMedGoogle Scholar
  143. 143.
    Levesque MC, Hobbs MR, Anstey NM, et al.: Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria. J Infect Dis 1999; 180:1994–2002.PubMedGoogle Scholar
  144. 144.
    Kun JFJ, Mordmuller B, Lell B, Lehman LG, Luckner D, Kremsner PG: Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria. Lancet 1998; 351:265–266.PubMedGoogle Scholar
  145. 145.
    Burgner D, Xu WM, Rockett K, et al.: Inducible nitric oxide synthase polymorphism and fatal cerebral malaria. Lancet 1998;352:1193–1194.PubMedGoogle Scholar
  146. 146.
    Xu WM, Liu LZ, Emson PC, Harrington CR, Charles IG: Evolution of a homopurine-homopyrimidine pentanucleotide repeat sequence opstream of the human inducible nitric oxide synthase gene. Gene 1997;204:165–170.PubMedGoogle Scholar
  147. 147.
    Sharara AI, Hunt CM, Hamilton JD: Hepatitis C [Review]. Ann Int Med 1996;125:658–668.PubMedGoogle Scholar
  148. 148.
    Akaike T, Noguchi Y, Ijiri S, et al.: Pathogenesis of influenza virusinduced pneumonia: involvement of bothnitric oxide and oxygen radicals. Proc Natl Acad Sci USA 1996;93:2448–2453.PubMedGoogle Scholar
  149. 149.
    Croen KD: Evidence for antiviral effect of nitric oxide. Inhibition of herpes simplex virus type 1 replication. J Clin Invest 1993;91:2446–2452.PubMedGoogle Scholar
  150. 150.
    Bi Z, Reiss CS: Inhibition of vesicular stomatitis virus infection by nitric oxide. J Virol 1995;69:2208–2213.PubMedGoogle Scholar
  151. 151.
    Karupiah G, Xie QW, Buller RM, Nathan C, Duarte C, MacMicking JD: Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Scince 1993;261:1445–1448.Google Scholar
  152. 152.
    Karupiah G, Harris N: Inhibition of viral replication by nitric oxide and its reversal by ferrous sullfate and tricarboxylic acid cycle metabolites. J Exp Med 1995;181:2171–2179.PubMedGoogle Scholar
  153. 153.
    Lowenstein CJ, Hill SL, Lafond-Walker A, et al.: Nitric oxide inhibits viral replication in murine myocarditis. J Clin Invest 1996; 97:1837–1843.PubMedGoogle Scholar
  154. 154.
    Melkova Z, Esteban M: Inhibition of vaccinia virus DNA replication by inducible expression of nitric oxide synthase. J Immunol 1995; 155:5711–5718.PubMedGoogle Scholar
  155. 155.
    Mannick JB: The antiviral role of nitric oxide. Res Immunol 1995;146:693–697.PubMedGoogle Scholar
  156. 156.
    Tucker PC, Griffin DE, Choi S, Bui N, Wesselingh S: Inhibition of nitric oxide synthesis increases mortality in Sindbis virus encephalitis. J Virol 1996:70:3972–3977.PubMedGoogle Scholar
  157. 157.
    Sharara AI, Perkins DJ, Misubonis MA, Chan SU, Dominitz JA, Weinberg JB: Interferon (IFN)alpha activation of human blood mononuclear cells in vitro and in vivo for nitric oxide synthase (NOS) type 2 mRNA and protein expression—possible relationship of induced NO S2 to the antihepatitis C effects of IFN-alpha in vivo. J Exp Med 1997;186:1495–1502.PubMedGoogle Scholar
  158. 158.
    Ding AH, Nathan CF, Stuehr DJ: Release of reactive nitrogen intermediates and reactive oxygen intermedi ates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol 1988;141:2407–2412.PubMedGoogle Scholar
  159. 159.
    Jiang H, Rummage JA, Zhou A, et al.: IFN-alpha beta reconstitutes the deficiency in lipid A-activated AKR macrophages for nitricoxide synthase. J Immunol 1996;157:305–312.PubMedGoogle Scholar
  160. 160.
    Zhou AO, Chen ZF, Rummage JA, et al.: Exogenous interferongamma induces endogenous synthesis of interferon-alpha and-beta by murine macrophages for induction of nitric oxide synthase. J Interferon Cytok Res 1995;15:897–904.Google Scholar
  161. 161.
    Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N: Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron [see comments]. Am J Gastroenterol 1994;89:986–988.PubMedGoogle Scholar
  162. 162.
    Ikura Y, Morimoto H, Johmura H, Fukui M, Sakurai M: Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C. Am J Gastroenterol 1996;91:1367–1373.PubMedGoogle Scholar
  163. 163.
    Piperno A, Sampietro M, Dalba R, et al.: Iron stores, response to alpha-interferon therapy, and effects of iron depletion inchronic hepatitis C. Liver 1996;16:248–254.PubMedGoogle Scholar
  164. 164.
    Weiss G, Werner-Felmayer G, Werner ER, Gruenewals K, Wachter H, Hentze MW: Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med 1994;180:969–976.PubMedGoogle Scholar
  165. 165.
    Morris LF, Lemak NA, Amett FC, Jr., Jordon RE, Duvic M: Systemic lupus ery the matosus diagnosed during interferon alfa therapy. South Med J 1996;89:810–814.PubMedGoogle Scholar
  166. 166.
    Nadir F, Fagiuoli S, Wright HI, et al.: Rheuma toid arthritis: a complication of interferon therapy. J Okla State Med Assoc 1994;87:228–230.PubMedGoogle Scholar
  167. 167.
    Vial T, Descotes J: Immunemediated side-effects of cytokines in humans. Toxicology 1995;105;31–57.PubMedGoogle Scholar
  168. 168.
    Wandl UB, Nagel-Hiemke M, May D, et. al.: Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders. Clin Immunol Immunopath 1992;65:70–74.Google Scholar
  169. 169.
    Ronnblom LE, Alm GV, Oberg K: Autoimmune phenomena in patients with malignant carcinoid tumors during interferon-alpha treatment. Acta Oncol 1991;30:537–540.PubMedGoogle Scholar
  170. 170.
    Levesque MC, Ward FE, Jeffery DR, Weinberg JB: Interferon-beta IA-induced polyarthritis in a patient with the HLA-DRB1 +0404 allele. Arth Rheum 1999;42:569–573.Google Scholar
  171. 171.
    Fong KY, Boey ML, Koh WH, Feng PH: Cytokine concentrations in the synovial fluid and plasma of rheumatoid arthritis patients: correlation with bony erosions. Clin Exp Rheumatol 1994;12:55–58.PubMedGoogle Scholar
  172. 172.
    Arvin AM, Miller JJd: Acid labile alpha-interferon in sera and synovial fluids from patients with juvenile arthritis. Arthritis Rheum 1984;27:582–585.PubMedGoogle Scholar
  173. 173.
    Hopkins SJ, Meager A: Cytokines in synovial fluid: II. The presence of tumournec rosis factor and interferon. Clin Exp Immunol 1988;73:88–92.PubMedGoogle Scholar
  174. 174.
    Lipsky PE, Davis LS, Cush JJ, Oppenheimer-Marks N: The role of cytokines in the pathogenesis of rheumatoid arthritis. Springer Semin Immunopathol 1989;11:123–162.PubMedGoogle Scholar
  175. 175.
    Maini RN, Taylor PC: Anticytokine therapy for rheumatoid arthritis. Ann Rev Med 2000;51:207–229.PubMedGoogle Scholar
  176. 176.
    Perkins DJ, St Clair EW, Misukonis MA, Weinberg JB: Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2). Arth Rheum 1998;41:2205–2210.Google Scholar
  177. 177.
    Fermor B, Weinberg JB, Pisetsky DS, Misukonis M, Banes AJ, Guilak F: The effects of static and dynamic compression on nitric oxide production in articular cartilage explants. J Orthop Res 2000, in press.Google Scholar
  178. 178.
    Fink C, Femor B, Weinberg JB, Pisetsky DS, Misukonis M, Guilak F: The effects of dynamic mechanical compression on nitric oxide production in the meniscus. Osteo Cart 2000; in press.Google Scholar

Copyright information

© Humana Press Inc 2000

Authors and Affiliations

  • J. Brice Weinberg
    • 1
  1. 1.Duke University and VA Medical CentersDurham

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