Interleukin-1β induction of c-fos and collagenase expression in articular chondrocytes: Involvement of reactive oxygen species

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Abstract
Interleukin‐1β (IL‐1) is implicated in cartilage destruction in arthritis through promotion of matrix metalloproteinase production. Upregulation of collagenase gene expression by IL‐1 is known to require the transactivators Fos and Jun. Recently, reactive oxygen species (ROS) have been suggested to act as intracellular signaling molecules mediating the biological effects of cytokines. Here, we demonstrated ROS production by IL‐1‐stimulated bovine chondrocytes and that neutralizing ROS activity by the potent antioxidant, N‐acetylcysteine, or inhibiting endogenous ROS production by diphenyleneiodonium (DPI), significantly attenuated IL‐1‐induced c‐fos and collagenase gene expression. The inhibitory effect of DPI implicates enzymes such as NADPH oxidase in the endogenous production of ROS. Chondrocytes were also found to produce 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‐NG‐monomethylarginine, a NO synthase inhibitor, partially inhibited IL‐1‐regulated collagenase expression. Moreover, treatment of chondrocytes 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 messengers transducing extracellular stimuli to their targets in the nucleus, leading to augmentation of gene expression. J. Cell. Biochem. 69:19–29, 1998.