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)


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.


Nitric Oxide Adjuvant Arthritis Cytosolic Phospholipase Arthritis Induction Endogenous Nitric Oxide 
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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

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