Antioxidants inhibit interleukin-1-induced cyclooxygenase and nitric-oxide synthase expression in rat mesangial cells. Evidence for post-transcriptional regulation.
Glomerular mesangial cells produce reactive oxygen intermediates when stimulated by interleukin-1 (IL-1) or tumor necrosis factor. Recent observations suggest that reactive oxygen intermediates may play a role in IL-1 and tumor necrosis factor signaling and may upregulate gene expression. We therefore evaluated the effects of antioxidants on IL-1beta-induced cyclooxygenase-2 (Cox-2) and inducible nitric-oxide synthase (iNOS) expression in rat mesangial cells. The oxidant scavenger, pyrrolidine dithiocarbamate (PDTC), inhibited iNOS expression at the transcriptional level, since PDTC abolished iNOS mRNA accumulation. In contrast, PDTC inhibited Cox-2 expression at the post-transcriptional level, since PDTC did not affect IL-1beta-induced Cox-2 mRNA levels but inhibited Cox-2 protein expression and prostaglandin E2 production. Another antioxidant, rotenone, which inhibits reactive oxygen intermediate production by inhibiting the mitochondrial electron transport system, did not inhibit IL-1beta-induced iNOS and Cox-2 mRNA expression but inhibited iNOS and Cox-2 protein expression, suggesting a post-transcriptional target for the inhibition of NOS and Cox-2 expression induced by IL-1beta. These results suggest that not only transcriptional regulation but also post-transcriptional mechanisms are involved in redox-sensitive inhibition of cytokine induced Cox-2 and NOS expression. These results suggest a novel approach for intervention in cytokine-mediated inflammatory processes.