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. 1996 Jun 1;97(11):2672–2679. doi: 10.1172/JCI118717

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

G D Anderson 1, S D Hauser 1, K L McGarity 1, M E Bremer 1, P C Isakson 1, S A Gregory 1
PMCID: PMC507355  PMID: 8647962

Abstract

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE2. PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.

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Selected References

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  1. Angel J., Berenbaum F., Le Denmat C., Nevalainen T., Masliah J., Fournier C. Interleukin-1-induced prostaglandin E2 biosynthesis in human synovial cells involves the activation of cytosolic phospholipase A2 and cyclooxygenase-2. Eur J Biochem. 1994 Nov 15;226(1):125–131. doi: 10.1111/j.1432-1033.1994.tb20033.x. [DOI] [PubMed] [Google Scholar]
  2. Billingham M. E. Models of arthritis and the search for anti-arthritic drugs. Pharmacol Ther. 1983;21(3):389–428. doi: 10.1016/0163-7258(83)90062-1. [DOI] [PubMed] [Google Scholar]
  3. Bombardieri S., Cattani P., Ciabattoni G., Di Munno O., Pasero G., Patrono C., Pinca E., Pugliese F. The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and nonsteroidal anti-inflammatory drugs. Br J Pharmacol. 1981 Aug;73(4):893–901. doi: 10.1111/j.1476-5381.1981.tb08743.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buchan G., Barrett K., Turner M., Chantry D., Maini R. N., Feldmann M. Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1 alpha. Clin Exp Immunol. 1988 Sep;73(3):449–455. [PMC free article] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Crofford L. J., Wilder R. L., Ristimäki A. P., Sano H., Remmers E. F., Epps H. R., Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, and corticosteroids. J Clin Invest. 1994 Mar;93(3):1095–1101. doi: 10.1172/JCI117060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davies P., Bailey P. J., Goldenberg M. M., Ford-Hutchinson A. W. The role of arachidonic acid oxygenation products in pain and inflammation. Annu Rev Immunol. 1984;2:335–357. doi: 10.1146/annurev.iy.02.040184.002003. [DOI] [PubMed] [Google Scholar]
  8. Feldmann M., Brennan F. M., Chantry D., Haworth C., Turner M., Abney E., Buchan G., Barrett K., Barkley D., Chu A. Cytokine production in the rheumatoid joint: implications for treatment. Ann Rheum Dis. 1990 Jun;49 (Suppl 1):480–486. [PubMed] [Google Scholar]
  9. Fletcher B. S., Kujubu D. A., Perrin D. M., Herschman H. R. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem. 1992 Mar 5;267(7):4338–4344. [PubMed] [Google Scholar]
  10. Fu J. Y., Masferrer J. L., Seibert K., Raz A., Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem. 1990 Oct 5;265(28):16737–16740. [PubMed] [Google Scholar]
  11. Geng Y., Blanco F. J., Cornelisson M., Lotz M. Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes. J Immunol. 1995 Jul 15;155(2):796–801. [PubMed] [Google Scholar]
  12. Hempel S. L., Monick M. M., Hunninghake G. W. Lipopolysaccharide induces prostaglandin H synthase-2 protein and mRNA in human alveolar macrophages and blood monocytes. J Clin Invest. 1994 Jan;93(1):391–396. doi: 10.1172/JCI116971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hirano T., Matsuda T., Turner M., Miyasaka N., Buchan G., Tang B., Sato K., Shimizu M., Maini R., Feldmann M. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988 Nov;18(11):1797–1801. doi: 10.1002/eji.1830181122. [DOI] [PubMed] [Google Scholar]
  14. Houssiau F. A., Devogelaer J. P., Van Damme J., de Deuxchaisnes C. N., Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988 Jun;31(6):784–788. doi: 10.1002/art.1780310614. [DOI] [PubMed] [Google Scholar]
  15. Jones D. A., Carlton D. P., McIntyre T. M., Zimmerman G. A., Prescott S. M. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 1993 Apr 25;268(12):9049–9054. [PubMed] [Google Scholar]
  16. Kaufmann W. E., Worley P. F., Pegg J., Bremer M., Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2317–2321. doi: 10.1073/pnas.93.6.2317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kujubu D. A., Herschman H. R. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem. 1992 Apr 25;267(12):7991–7994. [PubMed] [Google Scholar]
  18. Lee S. H., Soyoola E., Chanmugam P., Hart S., Sun W., Zhong H., Liou S., Simmons D., Hwang D. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem. 1992 Dec 25;267(36):25934–25938. [PubMed] [Google Scholar]
  19. Maier J. A., Hla T., Maciag T. Cyclooxygenase is an immediate-early gene induced by interleukin-1 in human endothelial cells. J Biol Chem. 1990 Jul 5;265(19):10805–10808. [PubMed] [Google Scholar]
  20. Masferrer J. L., Zweifel B. S., Manning P. T., Hauser S. D., Leahy K. M., Smith W. G., Isakson P. C., Seibert K. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3228–3232. doi: 10.1073/pnas.91.8.3228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Masferrer J. L., Zweifel B. S., Seibert K., Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest. 1990 Oct;86(4):1375–1379. doi: 10.1172/JCI114850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Meade E. A., Smith W. L., DeWitt D. L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993 Mar 25;268(9):6610–6614. [PubMed] [Google Scholar]
  23. O'Banion M. K., Sadowski H. B., Winn V., Young D. A. A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem. 1991 Dec 5;266(34):23261–23267. [PubMed] [Google Scholar]
  24. O'Neill G. P., Ford-Hutchinson A. W. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett. 1993 Sep 13;330(2):156–160. doi: 10.1016/0014-5793(93)80263-t. [DOI] [PubMed] [Google Scholar]
  25. O'Neill G. P., Mancini J. A., Kargman S., Yergey J., Kwan M. Y., Falgueyret J. P., Abramovitz M., Kennedy B. P., Ouellet M., Cromlish W. Overexpression of human prostaglandin G/H synthase-1 and -2 by recombinant vaccinia virus: inhibition by nonsteroidal anti-inflammatory drugs and biosynthesis of 15-hydroxyeicosatetraenoic acid. Mol Pharmacol. 1994 Feb;45(2):245–254. [PubMed] [Google Scholar]
  26. O'Sullivan M. G., Chilton F. H., Huggins E. M., Jr, McCall C. E. Lipopolysaccharide priming of alveolar macrophages for enhanced synthesis of prostanoids involves induction of a novel prostaglandin H synthase. J Biol Chem. 1992 Jul 25;267(21):14547–14550. [PubMed] [Google Scholar]
  27. Raz A., Wyche A., Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1657–1661. doi: 10.1073/pnas.86.5.1657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Raz A., Wyche A., Siegel N., Needleman P. Regulation of fibroblast cyclooxygenase synthesis by interleukin-1. J Biol Chem. 1988 Feb 25;263(6):3022–3028. [PubMed] [Google Scholar]
  29. Renz H., Gong J. H., Schmidt A., Nain M., Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol. 1988 Oct 1;141(7):2388–2393. [PubMed] [Google Scholar]
  30. Ristimäki A., Garfinkel S., Wessendorf J., Maciag T., Hla T. Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation. J Biol Chem. 1994 Apr 22;269(16):11769–11775. [PubMed] [Google Scholar]
  31. Robinson D. R., Tashjian A. H., Jr, Levine L. Prostaglandin-stimulated bone resorption by rheumatoid synovia. A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest. 1975 Nov;56(5):1181–1188. doi: 10.1172/JCI108195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sano H., Hla T., Maier J. A., Crofford L. J., Case J. P., Maciag T., Wilder R. L. In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. J Clin Invest. 1992 Jan;89(1):97–108. doi: 10.1172/JCI115591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Seibert K., Zhang Y., Leahy K., Hauser S., Masferrer J., Perkins W., Lee L., Isakson P. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12013–12017. doi: 10.1073/pnas.91.25.12013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Seitz M., Loetscher P., Dewald B., Towbin H., Ceska M., Baggiolini M. Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes--regulation by IFN-gamma and IL-4. J Immunol. 1994 Feb 15;152(4):2060–2065. [PubMed] [Google Scholar]
  35. Szczepanski A., Moatter T., Carley W. W., Gerritsen M. E. Induction of cyclooxygenase II in human synovial microvessel endothelial cells by interleukin-1. Inhibition by glucocorticoids. Arthritis Rheum. 1994 Apr;37(4):495–503. doi: 10.1002/art.1780370409. [DOI] [PubMed] [Google Scholar]
  36. Theisen-Popp P., Pape H., Müller-Peddinghaus R. Interleukin-6 (IL-6) in adjuvant arthritis of rats and its pharmacological modulation. Int J Immunopharmacol. 1992 May;14(4):565–571. doi: 10.1016/0192-0561(92)90117-4. [DOI] [PubMed] [Google Scholar]
  37. Van Snick J., Vink A., Cayphas S., Uyttenhove C. Interleukin-HP1, a T cell-derived hybridoma growth factor that supports the in vitro growth of murine plasmacytomas. J Exp Med. 1987 Mar 1;165(3):641–649. doi: 10.1084/jem.165.3.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Vane J. R., Mitchell J. A., Appleton I., Tomlinson A., Bishop-Bailey D., Croxtall J., Willoughby D. A. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2046–2050. doi: 10.1073/pnas.91.6.2046. [DOI] [PMC free article] [PubMed] [Google Scholar]

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