Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5␣-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6

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... r, in part, by inhibiting NFB activity. It did not appear that 5␣-dihydrotestosterone inhibited NFB by activating the androgen receptor to compete for the NFB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5␣-dihydrotestosterone repressed formation of NFB⅐NFB response element complex formation. In LNCaP prostate carcinoma cells, 5␣-dihydrotestosterone achieved this effect through maintenance of IB␣ protein levels in the face of phorbol ester, a stimulus that results in IB␣ degradation. Finally, we confirmed that IB␣ inhibits NFB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IB␣ levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.