Evidence for Activation of Cyclooxygenase-1/-2 by Endogenous Nitric Oxide in Adjuvant Arthritic Lewis Rats

  • Hermann-Josef Thierse
  • Walter-Gunar Friebe
  • Werner Scheuer
  • Wolfgang Voelter
  • Ulrich Tibes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 416)

Abstract

Increased enzyme activities of cytosolic phospholipase A2 (cPLA2) and nitric oxide synthase (NOS) have been implicated in the pathophysiology of rheumatoid arthritis(RA)1,2,3,4 and the alteration of immunological responses5,6. As determined on messenger RNA (mRNA) and protein level, in human rheumatoid synoviocytes, both, cPLA2 and growth factor-responsive prostaglandin H synthase-2 (PGHS-2 or cyclooxygenase-2, COX-2) activity were induced by interleukin-lβ, while secretory PLA2 (sPLA2) and constitutive prostaglandin H synthase-1 (PGHS-1 or cyclooxygenase-1, COX-1) remained unaffected. Reflecting the enhanced activity of this pathway, its induction was associated with high levels of prostaglandin-2 (PGE2), a mediator of pain and inflammation in the joints of patients with RA2. In addition, patients with RA showed high levels of nitrite (NO 2, breakdown product of nitric oxide) and 3-nitrotyrosine, indicating elevated NOS activity and nitric oxide (NO) dependent oxidative damage3,7. In order to evaluate a physiological link between cPLA2, COX-1/-2 and NOS pathway in vivo, we investigated the effect of L-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NOS, in adjuvant-induced arthritis in the rat, while dexamethasone served as control drug, This model exhibits several pathological features similar to those occurring in autoimmune reactive RA in humans, characterized by chronic inflammation of the joints. In our studies following parameters have been determined: i) PGE2 as a product of the PLA2 and COX-1/-2 pathway, ii) platelet-activating-factor (PAF, PAF-acether) as product of the PLA2 and acetyltransferase pathway, iii) NO 2 as product of the NOS pathway, iv) paw swelling as an indicator of in vivo response.

Keywords

Nitric Oxide Adjuvant Arthritis Cytosolic Phospholipase Arthritis Induction Endogenous Nitric Oxide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    U. Tibes, A. Vondran, E. Rodewald, W.-G. Friebe, W. Schäfer, and W. Scheuer, Inhibition of allergic and non-allergic inflammation by phospholipase A, inhibitors. Int.Arch.Allergy Immunol. 107. 432–434 (1995).PubMedCrossRefGoogle Scholar
  2. 2.
    K.I. Hulkower, S.J. Wertheimer,W. Lewin, J.W. Coffey, C.M. Anderson, T. Chen, D.L. DeWitt, R.M. Crowl, W.C. Hope, and D.W. Morgan, Interleukin-lß induces cytosolic phospholipase A2 and prostaglandin H synthase in rheumatoid synovial fibroblasts. Arthritis Rheum. 37. 653–661 (1994).PubMedCrossRefGoogle Scholar
  3. 3.
    H. Kaurr and B. Halliwell, Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. FEBS 350. 9–12. (1994).CrossRefGoogle Scholar
  4. 4.
    A. lalenti, S. Moncada, and M. Di Rosa, Modulation of adjuvant arthritis by endogenous nitric oxide. Br.J.Pharmacol. 110. 701–706. (1993).CrossRefGoogle Scholar
  5. 5.
    X. Wei, I.G. Charles, A. Smith, J. Ure, G.-j. Feng, F.-p. Huang, D. Xu, W. Muller, S. Moncada, and F.Y Liew, Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375. 408–411. (1995).PubMedCrossRefGoogle Scholar
  6. 6.
    J.D. MacMicking, C. Nathan, G. Hom, N. Chartrain, D.S. Fletcher, M. Trumbauer, K. Stevens, Q. Xie, K. Sokol, N. Hutchinson, H. Chen, and J.S. Mudgett, Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81. 641–650. (1995).PubMedCrossRefGoogle Scholar
  7. 7.
    A.J. Farrell, D.R. Blake, R.M.J. Palmer, and S. Moncada, Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann. Rheum. Dis. 51. 1219–1222. (1992).PubMedCrossRefGoogle Scholar
  8. 8.
    D.R. Janero and C. Burghardt, Solid-phase extraction on silica cartridges as an aid to platelet-activating factor enrichment and analysis. JChromatogr. 526. 11–24. (1990).CrossRefGoogle Scholar
  9. 9.
    D.J. Hanahan and S.T. Weintraub, Platelet-Activating Factor Isolation, Identification, and Assay. Methods of Biochem. Anal. 31. 195–219. (1985).CrossRefGoogle Scholar
  10. 10.
    M. Lepoivre, H. Boudbid, and J.-F. Petit, Antiproliferative activity of g-Interferon combined with lipopolysaccharide on murine adenocarcinoma: dependence on an L- arginine metabolism with production of nitrite and citrulline. Cancer Res. 49. 1970–1976. (1989).PubMedGoogle Scholar
  11. 11.
    W. Rehfeldt, R. Hass, and M. Goppelt-Struebe, Charaterization of phospholipase AZ in monocytic cell lines. Functional and biochemical aspects of membrane association. Biochem. J. 276. 631–636. (1991).PubMedGoogle Scholar
  12. 12.
    L.W. Tjoelker, C. Wilder, C. Eberhardt, D.M. Stafforini, G. Dietsch, B. Schimpf, S. Hooper, H.L. Trong, L.S. Cousens, G.A. Zimmerman, Y.Yamada, T.M. McIntyre, S.M. Prescott, and P.W. Gray, Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 374. 549–553. (1995).PubMedCrossRefGoogle Scholar
  13. 13.
    D. Salvemini, T.P. Misko, J.L. Masferrer, K. Seibert, M.G. Currie, and R Needleman, Nitric oxide activates cyclooxgenase enzymes. Proc. Natl. Acad. Sci. USA 90. 7240–7 244. (1993).Google Scholar
  14. 14.
    D. Salvemini, P.T. Manning, B.S. Zweifel, K. Seibert, J. Connor, M.G. Currie, R Needleman, and J.L. Mas-ferrer, Dual inhibition of nitric oxide and prostaglandin production contributes to the antiinflammatory properties of nitric oxide synthase inhibitors. J. Clin. Invest. 96. 301 (1995).PubMedCrossRefGoogle Scholar
  15. 15.
    H.-J. Thierse, W. Scheuer, A. Krusch, G.-W. Friebe, P. Gierschick, and U. Tibes, Major role of cPLA2, secondary of COX and NOS, minor roles of sPLA2 and PLC in experimental inflammation. Eicosanoids and other bioactive lipids in cancer, inflammation and radiation injury: 4th Intern. Conf. Hongkong. 42. (1995).Google Scholar
  16. 16.
    J.R. Vane, J.A. Mitchell, I. Appleton, A. Tomlinson, D. Bishop-Bailey, J. Croxtall and D.A. Willoughby, Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Natl. Acad. Sci. USA 91. 2046–2050 (1994).PubMedCrossRefGoogle Scholar
  17. 17.
    I. Wicks, G. McColl, and L. Harrison, New perspectives on rheumatoid arthritis. Immunol. Today 15. 553–556 (1994).PubMedCrossRefGoogle Scholar
  18. 18.
    J.R. Connor, P.T. Manning S.L. Settle, W.M. Moore G.M. Jerome, R.K. Webber, F. Siong Tjoeng, and M.G. Currie, Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase. Eur. J. Pharmacol. 273. 15–24 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Hermann-Josef Thierse
    • 1
    • 3
  • Walter-Gunar Friebe
    • 1
  • Werner Scheuer
    • 2
  • Wolfgang Voelter
    • 3
  • Ulrich Tibes
    • 1
  1. 1.Department of Preclinical ResearchBoehringer Mannheim GmbHMannheimGermany
  2. 2.Department of Immunology/OncologyBoehringer Mannheim GmbHPenzbergGermany
  3. 3.Department of BiochemistryUniversity of TübingenTübingenGermany

Personalised recommendations