INTERLEUKIN-1-BETA INDUCTION OF C-FOS AND COLLAGENASE EXPRESSION IN ARTICULAR CHONDROCYTES - INVOLVEMENT OF REACTIVE OXYGEN SPECIES

Interleukin-1 beta (IL-1) is implicated in cartilage destruction in ar thritis through promotion of matrix metalloproteinase production. Upre gulation of collagenase gene expression by IL-1 is known to require th e transactivators Fos and Jun. Recently, reactive oxygen species (ROS) have been suggested to act as intracellular signaling molecules media ting the biological effects of cytokines. Here, we demonstrated ROS pr oduction by IL-1-stimulated bovine chondrocytes and that neutralizing ROS activity by the potent antioxidant, N-acetylcysteine, or inhibitin g endogenous ROS production by diphenyleneiodonium (DPI), significantl y attenuated IL-1-induced c-fos and collagenase gene expression. The i nhibitory effect of DPI implicates enzymes such as NADPH oxidase in th e endogenous production of ROS. Chondrocytes were also found to produc e nitric oxide (NO) upon IL-1 stimulation. That NO may mediate part of the inducing effects of IL-1 was supported by the observation that L- N-G-monomethylarginine, a NO synthase inhibitor, partially inhibited I L-1-regulated collagenase expression. Moreover, treatment of chondrocy tes with the NO-producing agent, S-nitroso-N-acetylpenicillamine, was sufficient to induce collagenase mRNA levels. In summary, our results suggest that ROS released in response to IL-1 may function as second m essengers transducing extracellular stimuli to their targets in the nu cleus, leading to augmentation of gene expression. (C) 1998 Wiley-Liss , Inc.