NITRIC-OXIDE PRODUCTION AND INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION IN INFLAMMATORY ARTHRITIDES

In this study, we have identified the source of nitric oxide (NO) prod uced in the human inflammatory joints by analyzing expression of induc ible NO synthase. In ex vivo organ cultures, both inflammatory synoviu m and cartilage from patients with rheumatoid arthritis produced NO. T he NO production was suppressed by N-G-monomethyl-L-arginine, an inhib itor of NO synthase. The amount of NO produced by the synovium correla ted with the proportion of CD14(+) cells in the corresponding tissue ( r = 0.8, P < 0.05). Immunohistochemical analysis as well as in situ hy bridization showed that inducible NO synthase was predominantly expres sed in synovial lining cells, endothelial cells, chondrocytes, and to a lesser extent, in infiltrating mononuclear cells and synovial fibrob lasts. The synovial lining cells and the infiltrating cells expressing inducible NO synthase were identified where CD14(+) cells were locate d. Together with morphological features, this suggests that they are t ype A synoviocytes. NO production from freshly isolated synoviocytes a nd chondrocytes was up-regulated by in vitro stimulation with a combin ation of IL-TNF-beta, TNF-alpha, and LPS. In summary, the present resu lts suggest that NO is produced primarily by CD14(+) synoviocytes, cho ndrocytes, and endothelial cells in inflammatory joints of arthritides . NO production can be upregulated by cytokines present in inflamed jo ints. The increased NO production may thus tribute to the pathological features in inflammatory arthritides.