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. 1996 Jun;55(6):375–382. doi: 10.1136/ard.55.6.375

Interleukin-4 inhibits prostaglandin E2 production by freshly prepared adherent rheumatoid synovial cells via inhibition of biosynthesis and gene expression of cyclo-oxygenase II but not of cyclo-oxygenase I.

E Sugiyama 1, H Taki 1, A Kuroda 1, T Mino 1, N Yamashita 1, M Kobayashi 1
PMCID: PMC1010189  PMID: 8694577

Abstract

OBJECTIVE: To characterise the effect of interleukin-4 (IL-4) on the biosynthesis of cyclo-oxygenases I (COX I) and II (COX II), the rate limiting enzymes of the synthesis of prostaglandin E2 (PGE2), in freshly prepared rheumatoid synovial cells. METHODS: Adherent synovial cells were obtained from rheumatoid synovium by collagenase digestion. The concentrations of PGE2 in culture supernatants were determined by enzyme linked immunosorbent assay. The protein and mRNA concentrations of COX I and COX II were determined by Western blotting and reverse transcription polymerase chain reaction, respectively. RESULTS: Freshly prepared synovial cells produced large amounts of PGE2. They also showed increased gene expression of COX I and COX II, and synthesised these proteins. IL-4 had suppressive effects on the production of PGE2 by untreated or lipopolysaccharide (LPS) stimulated synovial cells. In addition, IL-4 inhibited the biosynthesis of COX II at the mRNA level. In contrast, it did not modify the protein concentration of COX I. In tests of cell specificity, IL-4 did not reduce the mRNA concentration of COX II in interleukin-1 alpha (IL-1 alpha) stimulated cultured synovial fibroblasts at passages 3-6, but it reduced considerably the mRNA concentrations of COX II in an LPS or IL-1 alpha stimulated U937 monocyte/macrophage cell line. CONCLUSIONS: These results suggest that IL-4 might inhibit overproduction of PGE2 in rheumatoid synovia via selective inhibition of the biosynthesis of COX II, and that this inhibition might be specific to macrophage-like synovial cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  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. Appleby S. B., Ristimäki A., Neilson K., Narko K., Hla T. Structure of the human cyclo-oxygenase-2 gene. Biochem J. 1994 Sep 15;302(Pt 3):723–727. doi: 10.1042/bj3020723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arend W. P., Dayer J. M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990 Mar;33(3):305–315. doi: 10.1002/art.1780330302. [DOI] [PubMed] [Google Scholar]
  4. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [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. Corcoran M. L., Stetler-Stevenson W. G., Brown P. D., Wahl L. M. Interleukin 4 inhibition of prostaglandin E2 synthesis blocks interstitial collagenase and 92-kDa type IV collagenase/gelatinase production by human monocytes. J Biol Chem. 1992 Jan 5;267(1):515–519. [PubMed] [Google Scholar]
  7. 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]
  8. Dayer J. M., Krane S. M., Russell R. G., Robinson D. R. Production of collagenase and prostaglandins by isolated adherent rheumatoid synovial cells. Proc Natl Acad Sci U S A. 1976 Mar;73(3):945–949. doi: 10.1073/pnas.73.3.945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DeWitt D. L. Prostaglandin endoperoxide synthase: regulation of enzyme expression. Biochim Biophys Acta. 1991 May 8;1083(2):121–134. doi: 10.1016/0005-2760(91)90032-d. [DOI] [PubMed] [Google Scholar]
  10. Donnelly R. P., Crofford L. J., Freeman S. L., Buras J., Remmers E., Wilder R. L., Fenton M. J. Tissue-specific regulation of IL-6 production by IL-4. Differential effects of IL-4 on nuclear factor-kappa B activity in monocytes and fibroblasts. J Immunol. 1993 Nov 15;151(10):5603–5612. [PubMed] [Google Scholar]
  11. Endo T., Ogushi F., Sone S., Ogura T., Taketani Y., Hayashi Y., Ueda N., Yamamoto S. Induction of cyclooxygenase-2 is responsible for interleukin-1 beta-dependent prostaglandin E2 synthesis by human lung fibroblasts. Am J Respir Cell Mol Biol. 1995 Mar;12(3):358–365. doi: 10.1165/ajrcmb.12.3.7873203. [DOI] [PubMed] [Google Scholar]
  12. Firestein G. S., Zvaifler N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 1990 Jun;33(6):768–773. doi: 10.1002/art.1780330602. [DOI] [PubMed] [Google Scholar]
  13. Hart P. H., Cooper R. L., Finlay-Jones J. J. IL-4 suppresses IL-1 beta, TNF-alpha and PGE2 production by human peritoneal macrophages. Immunology. 1991 Mar;72(3):344–349. [PMC free article] [PubMed] [Google Scholar]
  14. Hart P. H., Vitti G. F., Burgess D. R., Whitty G. A., Piccoli D. S., Hamilton J. A. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A. 1989 May;86(10):3803–3807. doi: 10.1073/pnas.86.10.3803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hla T., Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384–7388. doi: 10.1073/pnas.89.16.7384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hulkower K. I., Wertheimer S. J., Levin W., Coffey J. W., Anderson C. M., Chen T., DeWitt D. L., Crowl R. M., Hope W. C., Morgan D. W. Interleukin-1 beta induces cytosolic phospholipase A2 and prostaglandin H synthase in rheumatoid synovial fibroblasts. Evidence for their roles in the production of prostaglandin E2. Arthritis Rheum. 1994 May;37(5):653–661. doi: 10.1002/art.1780370508. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Miossec P., Briolay J., Dechanet J., Wijdenes J., Martinez-Valdez H., Banchereau J. Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum. 1992 Aug;35(8):874–883. doi: 10.1002/art.1780350805. [DOI] [PubMed] [Google Scholar]
  20. Miossec P., Naviliat M., Dupuy d'Angeac A., Sany J., Banchereau J. Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthritis Rheum. 1990 Aug;33(8):1180–1187. doi: 10.1002/art.1780330819. [DOI] [PubMed] [Google Scholar]
  21. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  22. Nakazato Y., Okada H., Sato A., Iwaita Y., Hayashida T., Hayashi M., Suzuki H., Saruta T. Interleukin 4 downregulates cell growth and prostaglandin release of human mesangial cells. Biochem Biophys Res Commun. 1993 Dec 15;197(2):486–493. doi: 10.1006/bbrc.1993.2505. [DOI] [PubMed] [Google Scholar]
  23. Niiro H., Otsuka T., Tanabe T., Hara S., Kuga S., Nemoto Y., Tanaka Y., Nakashima H., Kitajima S., Abe M. Inhibition by interleukin-10 of inducible cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: its underlying mechanism in comparison with interleukin-4. Blood. 1995 Jun 15;85(12):3736–3745. [PubMed] [Google Scholar]
  24. Paul W. E., Ohara J. B-cell stimulatory factor-1/interleukin 4. Annu Rev Immunol. 1987;5:429–459. doi: 10.1146/annurev.iy.05.040187.002241. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Smith W. L. Prostanoid biosynthesis and mechanisms of action. Am J Physiol. 1992 Aug;263(2 Pt 2):F181–F191. doi: 10.1152/ajprenal.1992.263.2.F181. [DOI] [PubMed] [Google Scholar]
  28. Smith W. L. The eicosanoids and their biochemical mechanisms of action. Biochem J. 1989 Apr 15;259(2):315–324. doi: 10.1042/bj2590315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sugiyama E., Kuroda A., Taki H., Ikemoto M., Hori T., Yamashita N., Maruyama M., Kobayashi M. Interleukin 10 cooperates with interleukin 4 to suppress inflammatory cytokine production by freshly prepared adherent rheumatoid synovial cells. J Rheumatol. 1995 Nov;22(11):2020–2026. [PubMed] [Google Scholar]
  30. Sugiyama E., Suzuki H., Tunru I. S., Yamashita N., Hori T., Kobayashi M. FK506, an immunosuppressant, partially inhibits interleukin 6 production by adherent rheumatoid synovial cells. J Rheumatol. 1994 Sep;21(9):1597–1601. [PubMed] [Google Scholar]
  31. Sundström C., Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976 May 15;17(5):565–577. doi: 10.1002/ijc.2910170504. [DOI] [PubMed] [Google Scholar]
  32. Suzuki H., Sugiyama E., Tunru I. S., Yamashita N., Matsuno H., Hamazaki T., Kobayashi M. Suppressive effect of interleukin-4 (IL-4) on IL-6 production by adherent rheumatoid synovial cells. Clin Immunol Immunopathol. 1993 Jan;66(1):67–72. doi: 10.1006/clin.1993.1009. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Warnock L. J., Hunninghake G. W. Multiple second messenger pathways regulate IL-1 beta-induced expression of PGHS-2 mRNA in normal human skin fibroblasts. J Cell Physiol. 1995 Apr;163(1):172–178. doi: 10.1002/jcp.1041630120. [DOI] [PubMed] [Google Scholar]
  35. Whittle B. J., Higgs G. A., Eakins K. E., Moncada S., Vane J. R. Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature. 1980 Mar 20;284(5753):271–273. doi: 10.1038/284271a0. [DOI] [PubMed] [Google Scholar]

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