Skip to main content
Log in

Endogenous nitric oxide and prostaglandin E2 do not regulate the synthesis of each other in interleukin-1β-stimulated rat articular cartilage

  • Original Articles
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Increased levels of nitric oxide (NO) and prostaglandins (PG) are present in the synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Interleukin-1β (IL-1) has been shown to induce the synthesis of both of these mediators. The present work was designed to study the interactions of NO and PGE2 synthesis induced by IL-1 in rat articular cartilage. Incubation of intact cartilage with IL-1 resulted in different dose response curves for NO and PGE2 synthesis. Two inhibitors of nitric oxide synthase N-monomethyl-L-arginine (L-NMMA) and L-N-iminoethyl-ornithine, (L-NIO), abolished the IL-1-induced nitrite production but failed to have any influence on the PGE2 synthesis. Exogenous NO, produced by two chemically different NO-releasing compounds (SIN-1 and GEA 3175) had no effect on PGE2 synthesis in articular cartilage. Dexamethasone and ketoprofen inhibited IL-1 induced PGE2 production, while nitrite synthesis remained unaltered. Acetylsalisylic acid (ASA) reduced PGE2 synthesis and had a slight inhibitory action also on NO production. In conclusion, our results show, that IL-1 induces the synthesis of both PGE2 and NO in articular cartilage but these two inflammatory mediators are not mediating the synthesis of one another.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Arend, W. P., andJ-M. Dayer. 1995. Inhibition of the production and effects of interleukin1 and tumor necrosis factor a in rehumatoid arthritis.Arthritis & Rheum. 38:151–160.

    Google Scholar 

  2. van de Loo, F. A. J., O. J. Arntz, A. C. Bakker, P. L. E. M. van Lent, M. J. M. Jacobs, andW. B. van den Berg. 1995. Role of interleukin 1 in antigen-induced exacerbations of murine arthritis.Am. J. Pathol. 146:239–249.

    PubMed  Google Scholar 

  3. Schmidt, H. H. H. W., andU. Walter. 1995. NO at work.Cell 78:919–925.

    Google Scholar 

  4. Stefanovic-Racic, M., J. Stadler, andC. H. Evans. 1993. Nitric oxide and arthritis.Arthritis & Rheum. 36:1036–1044.

    Google Scholar 

  5. Moilanen, E., andH. Vapaatalo. 1995. Nitric oxide in inflammation and immune reponse.Ann. Med. 27:359–367.

    PubMed  Google Scholar 

  6. Stadler, J., M. Stefanovic-Racic, T. R. Billiar, R. D. Curran, L. A. McIntyre, H. I. Georgescu, R. L. Simmons, andC. H. Evans. 1991. Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide.J. Immunol. 147:3915–3920.

    PubMed  Google Scholar 

  7. Charles, I. G., R. M. J. Palmer, M. S. Hickery, M. T. Bayliss, A. P. Chubb, V. S. Hall, D. W. Moss, andS. Moncada. 1993. Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte.Proc. Natl. Acad. Sci. U.S.A. 90:11419–11423.

    PubMed  Google Scholar 

  8. Maier, R., G. Bilbe, J. Rediske, andM. Lotz. 1994. Inducible nitric oxide synthase from human articular chondrocytes: cDNA cloning and analysis of mRNA expression.Biochem. Biophys. Acta 1208:145–150.

    PubMed  Google Scholar 

  9. Stefanovic-Racic, M., J. Stadler, H. I. Georgescu, andC. H. Evans. 1994. Nitric oxide synthesis and its regulation by rabbit synoviocytes.J. Rheumatol. 21:1892–1898.

    PubMed  Google Scholar 

  10. Farrell, A. J., D. R. Blake, R. M. J. Palmer, andS. Moncada. 1992. Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases.Ann. Rheum. Dis. 51:1219–1222.

    PubMed  Google Scholar 

  11. Kaur, H., andB. Halliwell. 1994. Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients.FEBS Lett. 350:9–12.

    PubMed  Google Scholar 

  12. Amin, A. R., P. E. DiCesare, P. Vyas, M. Attur, E. Tzeng, T. R. Billiar, S. A. Stuchin, andS. B. Abramson. 1995. The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: Evidence for up-regulated neuronal nitric oxide synthase.J. Exp. Med. 182:2097–2102.

    PubMed  Google Scholar 

  13. Taskiran, D., M. Stefanovic-Racic, H. Georgescu, andC. Evans. 1994. Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1.Biochem. Biophys. Res. Comm. 200:142–148.

    PubMed  Google Scholar 

  14. Hauselmann, H. J., L. Oppliger, B. A. Michel, M. Stefanovic-Racic, andC. H. Evans. 1994. Nitric oxide and proteoglycan biosynthesis by human articular chondrocytes in alginate cultures.FEBS Lett. 352:361–364.

    PubMed  Google Scholar 

  15. Järvinen, T. A. H., T. Moilanen, T. L.N. Järvinen, andE. Moilanen. 1995. Nitric oxide mediates IL-1 induced inhibition of glycosaminoglycan synthesis in rat articular cartilage.Med. Inflamm. 4:107–111.

    Google Scholar 

  16. Henry, Y., M. Lepoivre, J-C. Drapier, C. Ducroqo, J-L. Boucher, andA. Guissani. 1993. EPR characterization of molecular targets for NO in mammalian cells and organlles.FASEB J. 7:1124–1134.

    PubMed  Google Scholar 

  17. Karthein, R., W. Nastaincyzk, andH. H. Ruf. 1987. EPR study of ferric native prostaglandin H synthase and its ferrous NO derivative.Eur. J. Biochem. 166:173–180.

    PubMed  Google Scholar 

  18. Hajjar, D. P., H. M. Lander, S. F. A. Pearce, R. K. Upmacis, andK. B. Pomerantz. 1995. Nitric oxide enhances prostaglandin-H synthase-1 activity by a heme-independent mechanism—evidence implicating nitrosothiols.J. Am. Chem. Soc. 117:3340–3346.

    Google Scholar 

  19. Rettori, V., M. Gimeno, K. Lyson, andM. McCann. 1992. Nitric oxide mediates norepinephrine induced prostaglandin E2 release from the hypothalamus.Proc. Natl. Acad. Sci. U.S.A. 89:11543–11546.

    PubMed  Google Scholar 

  20. Salvemini, D., T. P. Misko, J. L. Masferrer, K. Seibert, M. G. Currie, andP. Needleman. 1993. Nitric oxide activates cyclooxygenase enzymes.Proc. Natl. Acad. Sci. U.S.A. 90:7240–7244.

    PubMed  Google Scholar 

  21. Riutta, A., J. Alanko, I. Mucha, andH. Vapaatalo. 1994. Effects of trolox C and SIN-1 on arachidonic acid metabolism and on cyclic GMP formation in leukocytes.Eur. J. Pharmacol. 262:217–222.

    PubMed  Google Scholar 

  22. Franchi, A. M., M. Chaud, V. Rettori, A. Suburo, andS. M. McCann. 1994. Role of nitric oxide in eicosanoid synthesis and uterine motility in estrogen-treated rat uteri.Proc. Natl. Acad. Sci. U.S.A. 91:439–543.

    PubMed  Google Scholar 

  23. Salvemini, D., K. Seibert, J. L. Masferrer, T. P. Misko, M. G. Currie, andP. Needleman. 1994. Endogenenous nitric oxide enhances prostaglandin production in a model of renal inflammation.J. Clin. Invest. 93:1940–1947.

    PubMed  Google Scholar 

  24. Kanner, J., S. Harel, andG. Granit. 1992. Nitric oxide, an inhibitor of lipid oxidation of lipoxygenase, cyclooxygenase and hemoglobin.Lipids 27:46–49.

    PubMed  Google Scholar 

  25. Stadler, J., B. G. Harbrecht, M. Di Silvio, P. D. Curran, M. L. Jordan, R. L. Simmonsa, andT. R. Billiar. 1993. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells.J. Leukoc. Biol. 53:165–172.

    PubMed  Google Scholar 

  26. Swierkosz, T. A., J. A. Mitchell, T. D. Warner, R. M. Botting, andJ. R. Vane. 1995. Co-induction of nitric oxide synthase and cyclo-oxygenase-interactions between nitric oxide and prostanoids.Br. J. Pharmacol. 114:1335–1342.

    PubMed  Google Scholar 

  27. Vane, J. R., J. A. Mitchell, I. Appleton, A. Tomlinson, D. Bishop-Bailey, J. Croxtall, andD. A. Willoughby. 1994. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation.Proc. Natl. Acad. Sci. U.S.A. 91:2046–2050.

    PubMed  Google Scholar 

  28. Tetsuka, T., D. Daphna-Iken, S. K. Srivastava, L. D. Baier, J. DuMaine, andA. R. Morrison. 1994. Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1.Proc. Natl. Acad. Sci. U.S.A. 91:12168–12172.

    PubMed  Google Scholar 

  29. Milano, S., F. Arcoleo, M. Dieli, R. Dagostino, G. Denucci, andE. Gillari. 1995. Prostaglandin E(2) regulates inducible nitric oxide synthase in the murine macrophage cell line J774.Prostaglandins 49:105–115.

    PubMed  Google Scholar 

  30. Kankaanranta, H., E. Rydell, A-S. Petersson, P. Holm, E. Moilanen, T. Corell, G. Karup, Vuorinen, S. B. Pedersen, A. Wennmalm, andT. Metsä-Ketelä. 1996. Nitric oxide-donating properties of mesoionic 3-aryl substituted oxatriazole-5-imine derivatives.Br. J. Pharmacol. 117:401–409.

    PubMed  Google Scholar 

  31. Ignarro, L. J., J. M. Fukuto, J. M. Griscavage, N. E. Rogers, andR. E. Byrns. 1993. Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine.Proc. Natl. Acad. Sci. U.S.A. 90:8103–8107.

    PubMed  Google Scholar 

  32. Green, L. C., D. A. Wagner, J. Glowgowski, P. L. Skeeper, J. S. Wishnok, andS. R. Tannenbaum. 1982. Analysis of nitrate, nitrite and [15N] nitrate in biological fluids.Anal. Biochem. 124:131–138.

    Google Scholar 

  33. Lyons-Giordano, B., M. A. Pratta, W. Galbraith, G. L. Davis, andE. C. Arner. 1993. Intereukin-1 differentially modulates chrondrocyte expression of cyclooxygenase-2 and phospholipase A2.Exp. Cell Res. 206:58–62.

    PubMed  Google Scholar 

  34. Crofford, L. J., R. L. Wilder, A. P. Ristimäki, H. Sano, E. F. Remmers, H. R. Epps, andT. Hla. 1994. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1β, phorbol ester, and corticosteroids.J. Clin. Invest. 93:1095–1101.

    PubMed  Google Scholar 

  35. Geng, Y., F. J. Blanco, M. Cornelisson, andM. Lotz. 1995. Regulation of cyclooxygenase- 2 expression in normal human articular chondrocytes.J. Immunol. 155:796–801.

    PubMed  Google Scholar 

  36. Berenbaum, F., C. Jacques, G. Thomas, M. T. Corvol, G. Béréziat, andJ. Masliah. 1996. Synergistic effect of interleukin-1β and tumor necrosis factorα on PGE2 production by articular chondrocytes does not involve PLA2 stimulation.Exp. Cell Res. 222:379–384.

    PubMed  Google Scholar 

  37. Masferrer, J. L., K. Seibert, B. Zweifel, andP. Needleman. 1992. Endogenous gluco-corticoids regulate an inducible cyclooxygenase enzyme.Proc. Natl. Acad. Sci. U.S.A. 89:3917–3921.

    PubMed  Google Scholar 

  38. Stefanovic-Racic, M., T. I. Morales, D. Taskiran, L. A. McIntyre, andC. H. Evans. 1996. The role of nitric oxide in proteoglycan turnover by bovine articular cartilage organ cultures.J. Immunol. 156:1213–1220.

    PubMed  Google Scholar 

  39. Palmer, R. M. J., T. Andrews, N. A. Foxwell, andS. Moncada. 1992. Glucocorticoids do not affect the induction of a novel calcium-dependent nitric oxide synthase in rabbit chondrocytes.Biochem. Biophys. Res. Comm. 188:209–215.

    PubMed  Google Scholar 

  40. Geng, Y., andM. Lotz. 1995. Increased intracellular Ca2+ selectively suppresses IL-1-induced NO production by reducing iNOS mRNA stability.J. Cell Biol. 129:1651–1657.

    PubMed  Google Scholar 

  41. Blanco, F. J., andM. Lotz. 1995. IL-1-induced nitric oxide inhibits chondrocyte proliferation via PGE2.Exp. Cell Res. 218:319–325.

    PubMed  Google Scholar 

  42. Geng, Y., R. Maier, andM. Lotz. 1995. Tyrosine kinases are involved with the expression of inducible nitric oxide synthase in human articular chondrocytes.J. Cell Physiol. 163:545–554.

    PubMed  Google Scholar 

  43. Meade, E. A., W. L. Smith, andD. L. DeWitt. 1993. Differential inhibition of prostaglandin endoperoxidase synthase (cyclooxygenase) isoenzymes by aspirin and other non-steroidal antiin-flammatory drugs.J. Biol. Chem. 268:6610–6614.

    PubMed  Google Scholar 

  44. Vane, J. 1994. Towards better aspirin.Nature 367:215–216.

    PubMed  Google Scholar 

  45. Seibert, K., Y. Zhang, K. Leahy, S. Hauser, J. Masferrer, W. Perkins, L. Lee, andP. Isakson. 1994. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.Proc. Natl. Acad. Sci. U.S.A. 91:12013–12017.

    PubMed  Google Scholar 

  46. Barnett, J., J. Chow, D. Ives, M. Chiou, R. Mackenzie, E. Osen, B. Nquyen, S. Tsing, C. Bach, J. Freire, H. Chan, E. Sigal, andC. Ramesha. 1994. Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system.Biochim. Biophys. Acta 1209:130–139.

    PubMed  Google Scholar 

  47. Gierse, J. K., S. D. Hauser, D. P. Creely, C. Koboldt, S. H. Rangwala, P. C. Isakson, andK. Seibert. 1995. Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase.Biochem. J. 305:479–484.

    PubMed  Google Scholar 

  48. Aeberhard, E. E., S. A. Henderson, N. S. Arabolos, J. M. Griscavage, F. E. Castro, C. T. Barrett, andL. J. Ignarro. 1995. Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible nitric oxide synthase gene.Biochem. Biophys. Res. Comm. 208:1053–1059.

    PubMed  Google Scholar 

  49. Amin, A. R., P. Vyas, M. Attur, J. Leszczynska-Piziak, I. R. Patel, G. Weissmann, andS. B. Abramson. 1995. The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase.Proc. Natl. Acad. Sci. U.S.A. 92:7926–7930.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Järvinen, T.A.H., Moilanen, T., Järvinen, T.L.N. et al. Endogenous nitric oxide and prostaglandin E2 do not regulate the synthesis of each other in interleukin-1β-stimulated rat articular cartilage. Inflammation 20, 683–692 (1996). https://doi.org/10.1007/BF01488804

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01488804

Keywords

Navigation