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(Received for publication, April 3, 1996, and in revised form, July 24, 1996)
From the Institute on Aging, Department of Medicine, University of
Wisconsin, Madison, Wisconsin 53706 and the Madison Veterans
Administration GRECC, Madison, Wisconsin 53705
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
Volume 271, Number 42,
Issue of October 18, 1996
pp. 26267-26275
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
B Activity through Maintenance of IB
Levels Contributes to Dihydrotestosterone-mediated Repression of the
Interleukin-6 Promoter
-dihydrotestosterone, through the androgen receptor, repressed
activation of the interleukin-6 promoter, in part, by inhibiting NF
B
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 NFB·NFB
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.
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