Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Sep 1;184(3):1173–1178. doi: 10.1084/jem.184.3.1173

Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients

PMCID: PMC2192765  PMID: 9064335

Abstract

Nitric oxide (NO) is an important inflammatory mediator in nonhuman animal models of rheumatoid arthritis (RA). The purpose of the present study was to determine whether blood mononuclear cells from patients with active RA (as compared to control subjects) have higher levels of NO synthase type 2 (NOS2) and produce more NO in vitro. Leukocytes from 25 RA patients and 20 normal subjects were examined. Arthritis activity was assessed by tender and swollen joint counts, duration of morning stiffness, patient assessment of pain, physician and patient global assessment of disease activity, the modified Stanford Health Assessment Questionnaire, and by blood levels of acute phase reactants. Blood mononuclear cell NOS enzyme activity/antigen content and nitrite/nitrate formation in vitro were measured. Blood mononuclear cells from RA patients had increased NOS activity and increased NOS2 antigen content as compared to those from normal subjects, and responded to interferon-gamma with increased NOS expression and nitrite/nitrate production in vitro. NOS activity of freshly isolated blood mononuclear cells correlated significantly with disease activity, as assessed by render and swollen joint counts. Our results demonstrate that patients with RA have systemic activation for NOS2 expression, and that the degree of activation correlates with disease activity. Increased NOS2 expression and NO generation may be important in the pathogenesis of RA.

Full Text

The Full Text of this article is available as a PDF (643.2 KB).

Selected References

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

  1. 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]
  2. Beckman J. S., Crow J. P. Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans. 1993 May;21(2):330–334. doi: 10.1042/bst0210330. [DOI] [PubMed] [Google Scholar]
  3. Clancy R. M., Abramson S. B. Nitric oxide: a novel mediator of inflammation. Proc Soc Exp Biol Med. 1995 Nov;210(2):93–101. doi: 10.3181/00379727-210-43927aa. [DOI] [PubMed] [Google Scholar]
  4. Connor J. R., Manning P. T., Settle S. L., Moore W. M., Jerome G. M., Webber R. K., Tjoeng F. S., Currie M. G. Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase. Eur J Pharmacol. 1995 Jan 24;273(1-2):15–24. doi: 10.1016/0014-2999(94)00672-t. [DOI] [PubMed] [Google Scholar]
  5. Conrad K. P., Joffe G. M., Kruszyna H., Kruszyna R., Rochelle L. G., Smith R. P., Chavez J. E., Mosher M. D. Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J. 1993 Apr 1;7(6):566–571. [PubMed] [Google Scholar]
  6. Cush J. J., Lipsky P. E. Cellular basis for rheumatoid inflammation. Clin Orthop Relat Res. 1991 Apr;(265):9–22. [PubMed] [Google Scholar]
  7. Evans C. H., Stefanovic-Racic M., Lancaster J. Nitric oxide and its role in orthopaedic disease. Clin Orthop Relat Res. 1995 Mar;(312):275–294. [PubMed] [Google Scholar]
  8. 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]
  9. Goodwin B. J., Weinberg J. B. Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters. J Clin Invest. 1982 Oct;70(4):699–706. doi: 10.1172/JCI110665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Greenwald R. A. Oxygen radicals, inflammation, and arthritis: pathophysiological considerations and implications for treatment. Semin Arthritis Rheum. 1991 Feb;20(4):219–240. doi: 10.1016/0049-0172(91)90018-u. [DOI] [PubMed] [Google Scholar]
  11. Hahn G., Stuhlmüller B., Hain N., Kalden J. R., Pfizenmaier K., Burmester G. R. Modulation of monocyte activation in patients with rheumatoid arthritis by leukapheresis therapy. J Clin Invest. 1993 Mar;91(3):862–870. doi: 10.1172/JCI116307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  13. Ialenti A., Moncada S., Di Rosa M. Modulation of adjuvant arthritis by endogenous nitric oxide. Br J Pharmacol. 1993 Oct;110(2):701–706. doi: 10.1111/j.1476-5381.1993.tb13868.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kaur H., Halliwell B. Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients. FEBS Lett. 1994 Aug 15;350(1):9–12. doi: 10.1016/0014-5793(94)00722-5. [DOI] [PubMed] [Google Scholar]
  15. Magrinat G., Mason S. N., Shami P. J., Weinberg J. B. Nitric oxide modulation of human leukemia cell differentiation and gene expression. Blood. 1992 Oct 15;80(8):1880–1884. [PubMed] [Google Scholar]
  16. Mannick J. B., Asano K., Izumi K., Kieff E., Stamler J. S. Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell. 1994 Dec 30;79(7):1137–1146. doi: 10.1016/0092-8674(94)90005-1. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  20. Palmer R. M., Hickery M. S., Charles I. G., Moncada S., Bayliss M. T. Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun. 1993 May 28;193(1):398–405. doi: 10.1006/bbrc.1993.1637. [DOI] [PubMed] [Google Scholar]
  21. Pincus T., Summey J. A., Soraci S. A., Jr, Wallston K. A., Hummon N. P. Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum. 1983 Nov;26(11):1346–1353. doi: 10.1002/art.1780261107. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Seitz M., Hunstein W. Enhanced prostanoid release from monocytes of patients with rheumatoid arthritis and active systemic lupus erythematosus. Ann Rheum Dis. 1985 Jul;44(7):438–445. doi: 10.1136/ard.44.7.438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Stadler J., Stefanovic-Racic M., Billiar T. R., Curran R. D., McIntyre L. A., Georgescu H. I., Simmons R. L., Evans C. H. Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J Immunol. 1991 Dec 1;147(11):3915–3920. [PubMed] [Google Scholar]
  25. 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]
  26. Stefanovic-Racic M., Stadler J., Evans C. H. Nitric oxide and arthritis. Arthritis Rheum. 1993 Aug;36(8):1036–1044. doi: 10.1002/art.1780360803. [DOI] [PubMed] [Google Scholar]
  27. Steven M. M., Lennie S. E., Sturrock R. D., Gemmell C. G. Enhanced bacterial phagocytosis by peripheral blood monocytes in rheumatoid arthritis. Ann Rheum Dis. 1984 Jun;43(3):435–439. doi: 10.1136/ard.43.3.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Stichtenoth D. O., Fauler J., Zeidler H., Frölich J. C. Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prednisolone. Ann Rheum Dis. 1995 Oct;54(10):820–824. doi: 10.1136/ard.54.10.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tamir S., deRojas-Walker T., Gal A., Weller A. H., Li X., Fox J. G., Wogan G. N., Tannenbaum S. R. Nitric oxide production in relation to spontaneous B-cell lymphoma and myositis in SJL mice. Cancer Res. 1995 Oct 1;55(19):4391–4397. [PubMed] [Google Scholar]
  30. Ueki Y., Miyake S., Tominaga Y., Eguchi K. Increased nitric oxide levels in patients with rheumatoid arthritis. J Rheumatol. 1996 Feb;23(2):230–236. [PubMed] [Google Scholar]
  31. 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]
  32. Weinberg J. B., Haney A. F. Spontaneous tumor cell killing by human blood monocytes and human peritoneal macrophages: lack of alteration by endotoxin or quenchers of reactive oxygen species. J Natl Cancer Inst. 1983 Jun;70(6):1005–1010. [PubMed] [Google Scholar]
  33. Weinberg J. B., Misukonis M. A., Shami P. J., Mason S. N., Sauls D. L., Dittman W. A., Wood E. R., Smith G. K., McDonald B., Bachus K. E. Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood. 1995 Aug 1;86(3):1184–1195. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES