Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides.

In this study, we have identified the source of nitric oxide (NO) produced in the human inflammatory joints by analyzing expression of inducible NO synthase. In ex vivo organ cultures, both inflammatory synovium and cartilage from patients with rheumatoid arthritis produced NO. The NO production was suppressed by NG-monomethyl-L-arginine, an inhibitor of NO synthase. The amount of NO produced by the synovium correlated with the proportion of CD14+ cells in the corresponding tissue (r = 0.8, P < 0.05). Immunohistochemical analysis as well as in situ hybridization showed that inducible NO synthase was predominantly expressed in synovial lining cells, endothelial cells, chondrocytes, and to a lesser extent, in infiltrating mononuclear cells and synovial fibroblasts. The synovial lining cells and the infiltrating cells expressing inducible NO synthase were identified where CD14+ cells were located. Together with morphological features, this suggests that they are type A synoviocytes. NO production from freshly isolated synoviocytes and chondrocytes was up-regulated by in vitro stimulation with a combination of IL-TNF-beta, TNF-alpha, and LPS. In summary, the present results suggest that NO is produced primarily by CD14+ synoviocytes, chondrocytes, and endothelial cells in inflammatory joints of arthritides. NO production can be upregulated by cytokines present in inflamed joints. The increased NO production may thus contribute to the pathological features in inflammatory arthritides.

[1]  M. Lotz,et al.  The inducible production of nitric oxide by articular cell types. , 1994, Osteoarthritis and cartilage.

[2]  C. Evans,et al.  N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats. , 1994, Arthritis and rheumatism.

[3]  A. Koch,et al.  Production of angiogenic activity by human monocytes requires an L-arginine/nitric oxide-synthase-dependent effector mechanism. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Y. Vodovotz,et al.  Mechanism of suppression of nitric oxide synthase expression by interleukin‐4 in primary mouse macrophages , 1994, Journal of leukocyte biology.

[5]  M. Seldin,et al.  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 , 1994, The Journal of experimental medicine.

[6]  Ian G. Charles,et al.  Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[7]  G. Panayi,et al.  Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. , 1993, Annals of the rheumatic diseases.

[8]  S. Wahl,et al.  Suppression of arthritis by an inhibitor of nitric oxide synthase , 1993, The Journal of experimental medicine.

[9]  F. Marumo,et al.  Induction of nitric oxide synthase gene by interleukin in vascular smooth muscle cells. , 1993, HYPERTENSION.

[10]  Ian G. Charles,et al.  Induction of nitric oxide synthase in human chondrocytes. , 1993, Biochemical and biophysical research communications.

[11]  L. Rorke,et al.  In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Levine,et al.  Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds. , 1993, Journal of immunology.

[13]  C. Lowenstein,et al.  Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J S Beckman,et al.  Peroxynitrite formation from macrophage-derived nitric oxide. , 1992, Archives of biochemistry and biophysics.

[15]  C. Lowenstein,et al.  Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. , 1992, American journal of respiratory cell and molecular biology.

[16]  S. Moncada,et al.  Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. , 1992, Annals of the rheumatic diseases.

[17]  L. Zhu,et al.  Bactericidal activity of peroxynitrite. , 1992, Archives of biochemistry and biophysics.

[18]  J. Weinberg,et al.  Nitric oxide modulation of human leukemia cell differentiation and gene expression. , 1992, Blood.

[19]  P. Villiger,et al.  Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. , 1992, The Journal of clinical investigation.

[20]  P. Neuhaus,et al.  Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat. , 1992, The Journal of clinical investigation.

[21]  R. Terkeltaub,et al.  Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. , 1992, Journal of immunology.

[22]  K. Rockett,et al.  Elevated secretion of reactive nitrogen and oxygen intermediates by inflammatory leukocytes in hyperacute experimental autoimmune encephalomyelitis: enhancement by the soluble products of encephalitogenic T cells , 1992, The Journal of experimental medicine.

[23]  M. Shichiri,et al.  Increased production of endothelin-1 in patients with inflammatory arthritides. , 1992, Arthritis and rheumatism.

[24]  T. Billiar,et al.  Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. , 1991, Journal of immunology.

[25]  Sherman Mp,et al.  Cytokine- and Pneumocystis carinii- induced L-arginine oxidation by murine and human pulmonary alveolar macrophages. , 1991 .

[26]  S S McCachren,et al.  Expression of metalloproteinases and metalloproteinase inhibitor in human arthritic synovium. , 1991, Arthritis and rheumatism.

[27]  M. Lotz,et al.  Transforming growth factor-beta and cellular immune responses in synovial fluids. , 1990, Journal of immunology.

[28]  R. Maki,et al.  Quantitative analysis of cytokine gene expression in rheumatoid arthritis. , 1990, Journal of immunology.

[29]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[30]  B. Freeman,et al.  Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  T. Billiar,et al.  Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells , 1989, The Journal of experimental medicine.

[32]  G. Firestein,et al.  Cytokines in chronic inflammatory arthritis. III. Rheumatoid arthritis monocytes are not unusually sensitive to gamma-interferon, but have defective gamma-interferon-mediated HLA-DQ and HLA-DR induction. , 1989, Arthritis and rheumatism.

[33]  I. Saito,et al.  Detection of Epstein-Barr virus DNA by polymerase chain reaction in blood and tissue biopsies from patients with Sjogren's syndrome , 1989, The Journal of experimental medicine.

[34]  D Hamerman,et al.  The biology of osteoarthritis. , 1989, The New England journal of medicine.

[35]  N. Miyasaka,et al.  Immunological and immunohistochemical analysis of rheumatoid nodules. , 1989, Annals of the rheumatic diseases.

[36]  T. Hirano,et al.  Excessive production of interleukin 6/B cell stimulatory factor‐2 in rheumatoid arthritis , 1988, European journal of immunology.

[37]  C. Nathan,et al.  Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. , 1988, Journal of immunology.

[38]  N. Miyasaka,et al.  Augmented interleukin-1 production and HLA-DR expression in the synovium of rheumatoid arthritis patients. Possible involvement in joint destruction. , 1988, Arthritis and rheumatism.

[39]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[40]  M. Marletta,et al.  Synthesis of nitrite and nitrate in murine macrophage cell lines. , 1987, Cancer research.

[41]  M. Marletta,et al.  Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[42]  H. Schumacher,et al.  Autopsy study correlating degree of osteoarthritis, synovitis and evidence of articular calcification. , 1984, The Journal of rheumatology.