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Suppression of Adjuvant Arthritis and Synovial Macrophage Inducible Nitric Oxide by N-iminoethyl-L-Ornithine, A Nitric Oxide Synthase Inhibitor

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Abstract

Nitric oxide NO⋅ is a pro-inflammatory effector molecule in certain inflammatory diseases, including arthritis. We investigated the production of NO⋅ by adjuvant arthritis (AA) synovial macrophages, and studied the effects of a NO⋅ synthase inhibitor, N-iminoethyl-L-ornithine (L-NIO). Compared to control rats, rats treated with L-NIO in vivo exhibited significantly lower articular index (p < 0.05), paw volume (p < 0.05), and synovial fluid cell count (p < 0.05). No effect on cutaneous delayed-type hypersensitivity to the disease-initiating antigen was observed. Inducible NO⋅ synthase (iNOS) was detected in AA synovial macrophages, and cultured AA synovial macrophage iNOS levels were increased by a factor of 138 ± 17% (p < 0.01) by 1 μg/ml LPS in vitro. Constitutive NO⋅ production by AA synovial macrophages (43 ± 1 nmol/105 cells/24 h) was significantly inhibited by 10 mM L-NIO in vitro (32 ± 0.5, p<0.01). NO⋅ production induced by 1 μg/ml LPS (48 ± 2) was also decreased by L-NIO (39 ± 2, p<0.05). In vivo L-NIO treatment also inhibited alveolar macrophage NO⋅ production (p < 0.05). The ability of L-NIO to decrease iNOS-mediated synovial macrophage NO⋅ production and inhibit the clinical parameters of AA implicate macrophage-derived NO⋅ in the pathogenesis of this disease.

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REFERENCES

  1. MONCADA S., R. M. J. PALMER, and E. A. HIGGS. 1991. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142.

    Google Scholar 

  2. HIBBS, J. B., R. R. TAINTOR, Z. VAVRIN, D. L. GRANGER, J. C. DRAPIER, I. J. AMBER, and J. R. LANCASTER. JR. Synthesis of NO from a terminal guanidino nitrogen atom of {s cL}-arginine: a molecular mechanism regulating cellular proliferation that targets intracellular iron. In NO from {s cL}-arginine: a Bioregulatory system. Ed. Moncada S. and Higgs E. A. pp. 189–223, Amsterdam: Elsevier.

  3. HIBBS, J. B. JR. R. R. TAINTOR, A. VAVRIN, and E. M. RACHLIN. 1988. NO: a cytotoxic activated macrophage effector molecule. Biochem. Biophys. Res. Commun. 157:87–94.

    Google Scholar 

  4. MC CALL T. B., N. K. BOUGHTON-SMITH, R. M. J. PALMER, B. J. R. WHITTLE, and S. MONCADA. 1989. Synthesis of NO fromL-arginine by neutrophils. Release and interaction with superoxide anion. Biochem. J. 261:293–296.

    Google Scholar 

  5. WEI, X. Q., I. G. CHARLES, A. SMITH, J. URE, G. FENY, F. HUANG, D. XU., W. MULLER, S. MONCADA, and F. Y. LLEW. 1992. Altered immune response in mice lacking iNOS. Nature 375:408–411.

    Google Scholar 

  6. HOFFMAN, R. A., J. M. LANGREHR, T. R. BILLAR, R. D. CURRAN, and R. L. SIMMONS. 1990. Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of {s cL}-arginine. J. Immunol. 145:2220–2226.

    Google Scholar 

  7. KUBES, T., M. SUZUKI, and D. N. GRANGER. 1991. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc. Natl. Acad. Sci. U.S.A. 88:4651–4655.

    Google Scholar 

  8. MULLIGAN, M. S., S. MONCADA, and P. A. WARD. 1992. Protective effects of inhibitors of nitric oxide synthase in immune complex vasculitis. Br. J. Pharmacol. 107:1159–1162.

    Google Scholar 

  9. MAC MICKING, J. D., D. O. WILLENBORG, M. J. WEIDEMANN, K. A. ROCKETT, and W. B. COWDEN. 1992. Elevated secretion of reactive nitrogen and oxygen intermediates by inflammatory leukocytes in hyperacute experimental autoimmune encephalomyelitis: enhancement by the soluble products of encephalotigenic T cells. J. Exp. Med. 176:303–310.

    Google Scholar 

  10. CATTEL, V., T. COOK, and S. MONCADA. 1990. Glomeruli synthesize nitrite in experimental nephrotoxic nephritis. Kidney Intl. 38:1056–1060.

    Google Scholar 

  11. FIRESTEIN, G. S. Rheumatoid synovitis and pannus. In Klippel, J. H., Dieppe P. A. (eds), 1994, Rheumatology, Mosby-Year Book, Philadelphia, 3.12.1–3.12.30.

    Google Scholar 

  12. FIRESTEIN, G. S. 1991. The immunopathogenesis of rheumatoid arthritis. Curr. Opin. Rheumatol. 3:398–406.

    Google Scholar 

  13. SANTOS L. and P. G. TIPPING. 1994. Attenuation of adjuvant arthritis in rats by treatment with oxygen radical scavengers. Immunol. Cell Biol. 72:406–414.

    Google Scholar 

  14. FARRELL, A. J., D. R. BLAKE, R. M. PALMER, and S. MONCADA. 1992. Increased concentration of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann. Rheum. Dis. 51:219–222.

    Google Scholar 

  15. STICHTENOTH, D. O., F. M. GUTZKI, D. TSIKAS, N. SELVE, S. M. BODE-BOGER, R. H. BOGER, and J. C. FORLICH. 1994. Increased urinary nitrate excretion in rats with adjuvant arthritis. Ann. Rheum. Dis. 53:547–549.

    Google Scholar 

  16. CENCI, E., L. ROMANI, A. MENCACCI, R. SPACCAPELO, E. SCHIAFFELLA, P. PUCCETTI, and F. BISTONI. 1993. Interleukin-4 and interleukin-10 inhibit nitric oxide-dependent macrophage killing of Candida albicans. Eur. J. Immunol. 23:1034–1038.

    Google Scholar 

  17. MORAND, E. F., P. HUTCHINSON, A. HARGREAVES, N. J. GOULDING, N. W. BOYCE, and S. R. HOLDSWORTH. 1995. Detection of intracellular lipocortin 1 in human leukocyte subsets. Clin. Immunol. Immunopathol. 76:195–202.

    Google Scholar 

  18. OSWALD, I. P., R. T. GAZZINELLI, and S. L. JAMES. 1992. IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J. Immunol. 148:3578–3581.

    Google Scholar 

  19. LIEW F.Y., Y. LI, D. MOSS, C. PARKINSON, M. V. ROGERS, and S. MONCADA. 1991. Resistance to Leishmania major infection correlates with the induction of NOS in murine macrophages. Eur. J. Immunol. 21:3009–3014.

    Google Scholar 

  20. BELENKY, S. N., R. A. ROBBINS, and I. RUBINSTEIN. 1993. Nitric oxide synthase inhibitors attenuate human monocyte chemotaxis in vitro. J. Leukocyte Biol. 53:498–503.

    Google Scholar 

  21. LEIBOVICH, S. J., P. J. POLVERINI, T. W. FONG, L. A. HARLOW, and A. E. KOCH. 1994. Production of angiogenic activity by human monocytes requires anL-arginine/nitric oxide-synthase-dependent effector mechanism. Proc. Natl. Acad. Sci. U.S.A. 91:4190–4194.

    Google Scholar 

  22. DUGAS B., M. DJAVAD MOSSALAYI, C. DAMAIS, and J. P. KOLB. 1995. Nitric oxide production by human monocytes: evidence for a role of CD23. Immunol. Today 16:574–580.

    Google Scholar 

  23. HIBBS J. B., Z. VAVRIN, and R. R. TAINTOR. 1987. {atL-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells}. J. Immunol. 138:550–565.

    Google Scholar 

  24. IALENTI, A., A. IANARO, S. MONCADA, and M. DI ROSA. 1992. Modulation of acute inflammation by endogenous nitric oxide. Eur. J. Pharmacol. 211:177–182.

    Google Scholar 

  25. CATTELL, V., P. LARGEN, E. DE HEER, and T. COOK. 1991. Glomeruli synthesize nitrite in active Heymann nephritis; the source is infiltrating macrophages. Kidney Intl. 40:847–851.

    Google Scholar 

  26. MULLIGAN, M. S., S. MONCADA, and P. A. WARD. 1992. Protective effects of inhibitors of NOS in immune complex-induced vasculitis. Br. J. Pharmacol. 107:1159–1162.

    Google Scholar 

  27. MC CARTNEY-FRANCIS, N., J. B. ALLEN, D. E. MIZEL, J. E. ALBINA, Q. W. XIE, C. F. NATHAN, and S. M. WAHL. 1993. Suppression of arthritis by an inhibitor of NOS. J. Exp. Med. 178:749–754.

    Google Scholar 

  28. REES, D. D., R. M. J. PALMER, R. SCHULZ, H. F. HODSON, and S. MONCADA. 1990. Characterization of three inhibitors of endothelial NOS in vitro and in vivo. Br. J. Pharmacol. 101:746–752.

    Google Scholar 

  29. MC CALL, T. B., FEELISCH, M., PALMER, R. M. J., and MONCADA, S. 1991. Identification of L-NIO as an irreversible inhibitor of NOS in phagocytic cells. Br. J. Pharmacol. 102:234–238.

    Google Scholar 

  30. STEFANOVIC-RACIC M., K. MEYERS, C. MESCHTER, J. W. COFFEY, R. A. HOFFMAN, and C. H. EVANS. 1994. N-Monomethyl-L-arginine, an inhibitor of NOS, suppresses the development of AA in rats. Arthritis Rheum 37:1062–1069.

    Google Scholar 

  31. OYANAGIU Y. 1994. NO and superoxide radical are involved in both initiation and development of AA in rats. Life Sci. 54:285–289.

    Google Scholar 

  32. IALENTI, A., S. MONCADA, and M. DI ROSA. 1993. Modulation of AA by endogenous NO. Br. J. Pharmacol. 110:701–706.

    Google Scholar 

  33. KLEBANOFF S. J. and C. F. NATHAN. 1993. Nitrite production by stimulated human polymorphonuclear leukocytes supplemented with azide and catalase. Biochem. Biophys. Res. Commun. 197:192–196.

    Google Scholar 

  34. BECKMAN J. S., T. W. BECKMAN, J. CHEN, and P. A. MARSHALL. 1990. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. U.S.A. 87:1620–1624.

    Google Scholar 

  35. SANTOS, L. L., E. F. MORAND, P. HUTCHINSON, N. W. BOYCE, and S. R. HOLDSWORTH. 1997. Anti-neutrophil monoclonal antibody therapy inhibits the development of adjuvant arthritis. Clin. Exp. Immunol. 107:248–254.

    Google Scholar 

  36. SAKURAI, H., H. KOHSAKA, M.-F. LIU, H. HIGASHIYAMA, Y. HIRATA, K. KANNO, I. SAITO, and N. MIYASAKA. 1995. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J. Clin. Invest. 96:2357–2363.

    Google Scholar 

  37. TASKIRAN, D., M. STEFANOVIC-RACIC, H. GEORGESCU, C. EVANS. 1994. Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem. Biophys. Res. Commun. 200:142–148.

    Google Scholar 

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Authors and Affiliations

  1. Centre for Inflammatory Diseases, Monash Medical Centre, Australia

    Leilani L. Santos, Eric F. Morand, Yuanhang Yang, Paul Hutchinson & Stephen R. Holdsworth

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Santos, L.L., Morand, E.F., Yang, Y. et al. Suppression of Adjuvant Arthritis and Synovial Macrophage Inducible Nitric Oxide by N-iminoethyl-L-Ornithine, A Nitric Oxide Synthase Inhibitor. Inflammation 21, 299–311 (1997). https://doi.org/10.1023/A:1027397816209

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