Abstract
We have demonstrated spontaneous nitric oxide (NO) production by primary synovial cultures from rheumatoid (RA) and osteoarthritis patients. Increased NO production followed addition of staphylococcal enterotoxin B. Immunochemical double staining with specific anti-human inducible NO synthase (iNOS) and nonspecific esterase (NSE), or anti- CD68 (markers for tissue macrophages) showed that although many lining layer cells in RA synovium expressed iNOS, most (approximately 90%) were NSE- and CD68-, with only a minor population (approximately 10%) which were iNOS+, CD68+/NSE+. These data demonstrate the capacity for high output of NO by human synovial tissue and show that, although human macrophages can express high levels of iNOS, the majority of cells expressing iNOS are fibroblasts. We also report that synoviocytes, and macrophage cell lines, cultured with the NO donor, S- nitroso-acetyl penicillamine, produced high concentrations of tumor necrosis factor (TNF)-alpha. These results suggest that NO may mediate pathology in RA through the induction of TNF-alpha production.
Full Text
The Full Text of this article is available as a PDF (2.4 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- Barnes P. J., Liew F. Y. Nitric oxide and asthmatic inflammation. Immunol Today. 1995 Mar;16(3):128–130. doi: 10.1016/0167-5699(95)80128-6. [DOI] [PubMed] [Google Scholar]
- Brennan F. M., Chantry D., Jackson A., Maini R., Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989 Jul 29;2(8657):244–247. doi: 10.1016/s0140-6736(89)90430-3. [DOI] [PubMed] [Google Scholar]
- Charles I. G., Palmer R. M., Hickery M. S., Bayliss M. T., Chubb A. P., Hall V. S., Moss D. W., Moncada S. Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11419–11423. doi: 10.1073/pnas.90.23.11419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dugas B., Mossalayi M. D., Damais C., Kolb J. P. Nitric oxide production by human monocytes: evidence for a role of CD23. Immunol Today. 1995 Dec;16(12):574–580. doi: 10.1016/0167-5699(95)80080-8. [DOI] [PubMed] [Google Scholar]
- Elliott M. J., Maini R. N., Feldmann M., Kalden J. R., Antoni C., Smolen J. S., Leeb B., Breedveld F. C., Macfarlane J. D., Bijl H. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994 Oct 22;344(8930):1105–1110. doi: 10.1016/s0140-6736(94)90628-9. [DOI] [PubMed] [Google Scholar]
- Farrell A. J., Blake D. R., Palmer R. M., Moncada S. Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis. 1992 Nov;51(11):1219–1222. doi: 10.1136/ard.51.11.1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feldmann M., Brennan F. M., Maini R. N. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440. doi: 10.1146/annurev.immunol.14.1.397. [DOI] [PubMed] [Google Scholar]
- Grabowski P. S., England A. J., Dykhuizen R., Copland M., Benjamin N., Reid D. M., Ralston S. H. Elevated nitric oxide production in rheumatoid arthritis. Detection using the fasting urinary nitrate:creatinine ratio. Arthritis Rheum. 1996 Apr;39(4):643–647. doi: 10.1002/art.1780390416. [DOI] [PubMed] [Google Scholar]
- Huang F. P., Feng G. J., Lindop G., Stott D. I., Liew F. Y. The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. J Exp Med. 1996 Apr 1;183(4):1447–1459. doi: 10.1084/jem.183.4.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Häuselmann H. J., Oppliger L., Michel B. A., Stefanovic-Racic M., Evans C. H. Nitric oxide and proteoglycan biosynthesis by human articular chondrocytes in alginate culture. FEBS Lett. 1994 Oct 3;352(3):361–364. doi: 10.1016/0014-5793(94)00994-5. [DOI] [PubMed] [Google Scholar]
- Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
- McCartney-Francis N., Allen J. B., Mizel D. E., Albina J. E., Xie Q. W., Nathan C. F., Wahl S. M. Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med. 1993 Aug 1;178(2):749–754. doi: 10.1084/jem.178.2.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McInnes I. B., al-Mughales J., Field M., Leung B. P., Huang F. P., Dixon R., Sturrock R. D., Wilkinson P. C., Liew F. Y. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996 Feb;2(2):175–182. doi: 10.1038/nm0296-175. [DOI] [PubMed] [Google Scholar]
- Merryman P. F., Clancy R. M., He X. Y., Abramson S. B. Modulation of human T cell responses by nitric oxide and its derivative, S-nitrosoglutathione. Arthritis Rheum. 1993 Oct;36(10):1414–1422. doi: 10.1002/art.1780361014. [DOI] [PubMed] [Google Scholar]
- Moncada S., Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. doi: 10.1056/NEJM199312303292706. [DOI] [PubMed] [Google Scholar]
- Mueller J., Brun del Re G., Buerki H., Keller H. U., Hess M. W., Cottier H. Nonspecific acid esterase activity: a criterion for differentiation of T and B lymphocytes in mouse lymph nodes. Eur J Immunol. 1975 Apr;5(4):270–274. doi: 10.1002/eji.1830050411. [DOI] [PubMed] [Google Scholar]
- Murrell G. A., Doland M. M., Jang D., Szabo C., Warren R. F., Hannafin J. A. Nitric oxide: an important articular free radical. J Bone Joint Surg Am. 1996 Feb;78(2):265–274. [PubMed] [Google Scholar]
- Murrell G. A., Jang D., Williams R. J. Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem Biophys Res Commun. 1995 Jan 5;206(1):15–21. doi: 10.1006/bbrc.1995.1003. [DOI] [PubMed] [Google Scholar]
- Nathan C., Xie Q. W. Regulation of biosynthesis of nitric oxide. J Biol Chem. 1994 May 13;269(19):13725–13728. [PubMed] [Google Scholar]
- Nicholson S., Bonecini-Almeida M. da G., Lapa e Silva J. R., Nathan C., Xie Q. W., Mumford R., Weidner J. R., Calaycay J., Geng J., Boechat N. Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med. 1996 May 1;183(5):2293–2302. doi: 10.1084/jem.183.5.2293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sakurai H., Kohsaka H., Liu M. F., Higashiyama H., Hirata Y., Kanno K., Saito I., Miyasaka N. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest. 1995 Nov;96(5):2357–2363. doi: 10.1172/JCI118292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schneemann M., Schoedon G., Hofer S., Blau N., Guerrero L., Schaffner A. Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis. 1993 Jun;167(6):1358–1363. doi: 10.1093/infdis/167.6.1358. [DOI] [PubMed] [Google Scholar]
- Stefanovic-Racic M., Meyers K., Meschter C., Coffey J. W., Hoffman R. A., Evans C. H. N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats. Arthritis Rheum. 1994 Jul;37(7):1062–1069. doi: 10.1002/art.1780370712. [DOI] [PubMed] [Google Scholar]
- Stefanovic-Racic M., Morales T. I., Taskiran D., McIntyre L. A., Evans C. H. The role of nitric oxide in proteoglycan turnover by bovine articular cartilage organ cultures. J Immunol. 1996 Feb 1;156(3):1213–1220. [PubMed] [Google Scholar]
- Stefanovic-Racic M., Stadler J., Georgescu H. I., Evans C. H. Nitric oxide synthesis and its regulation by rabbit synoviocytes. J Rheumatol. 1994 Oct;21(10):1892–1898. [PubMed] [Google Scholar]
- Trede N. S., Geha R. S., Chatila T. Transcriptional activation of IL-1 beta and tumor necrosis factor-alpha genes by MHC class II ligands. J Immunol. 1991 Apr 1;146(7):2310–2315. [PubMed] [Google Scholar]
- Weinberg J. B., Granger D. L., Pisetsky D. S., Seldin M. F., Misukonis M. A., Mason S. N., Pippen A. M., Ruiz P., Wood E. R., Gilkeson G. S. The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. J Exp Med. 1994 Feb 1;179(2):651–660. doi: 10.1084/jem.179.2.651. [DOI] [PMC free article] [PubMed] [Google Scholar]