The effects of altering intracellular redox potential on interleukin 1 (IL-1)-induced MCP-1 gene expression by human mesangial cells were examined. Thiol containing antioxidants significantly increased cellular glutathione content while decreasing glutathione disulfide levels. These antioxidants inhibited IL-1 induction of MCP-1 mRNA expression. This correlated with a decrease in DNA binding activity of NF-kappa B, a transcription factor thought to be necessary for MCP-1 gene expression. Incubation of mesangial cells with the oxidizing agents diamide or hydrogen peroxide did not upregulate MCP-1 gene expression, and prevented IL-1 induction of MCP-1 mRNA. Oxidants appeared to inhibit the degradation of I kappa B, and the translocation of NF-kappa B to the nucleus. Non-oxidative depletion of intracellular glutathione also attenuated the effects of IL-1 on MCP-1 expression. These data indicate that the intracellular redox potential is a critical determinant of cell activation by IL-1. The observation that both oxidizing and reducing environments are inhibitory suggests that redox changes can affect the IL-1 signal transduction pathway at multiple points.