INVOLVEMENT OF REACTIVE OXYGEN SPECIES IN CYTOKINE AND GROWTH-FACTOR INDUCTION OF C-FOS EXPRESSION IN CHONDROCYTES

The cytokine tumor necrosis factor alpha (TNF alpha) and the growth fa ctor basic fibroblast growth factor (bFGF) are known to induce early r esponse genes such as c-fos and c-jun in various cell types. Activatio n of AP-1, a heterodimeric complex of Fos and Jun proteins, is require d for matrix metalloproteinase production and cell proliferation. Howe ver, the signaling pathways by which these two factors influence the e xpression and activities of AP-1 remain currently poorly characterized . Several studies have shown that cytokines induce reactive oxygen spe cies (ROS) production, but growth factor induction of ROS has not been reported. In the present study we demonstrate that both TNF alpha and bFGF induce ROS production, and that this is a common signaling event involved in the stimulation of c-fos gene expression in chondrocytes. To our knowledge, this is the first report directly demonstrating ROS production upon stimulation with a growth factor. TNF alpha and bFGF induction of ROS production is mediated through flavonoid-containing e nzymes such as NADPH oxidase. Moreover, the ROS nitric oxide is not re sponsible for the induction of c-fos expression by TNF alpha and bFGF. In addition, the inhibitory effects of antioxidants on c-fos expressi on may account for their protective roles against proliferative and in flammatory diseases such as cancer, cardiovascular diseases, and arthr itis.