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Molecular and Cellular Biology, April 2004, p. 2593-2604, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2593-2604.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Mechanism of Suppression of Testicular Steroidogenesis by Proinflammatory Cytokine Tumor Necrosis Factor Alpha

Cheol Yi Hong,1 Jin Hee Park,1 Ryun Seop Ahn,1 Suhn Young Im,2 Hueng-Sik Choi,1 Jaemog Soh,2 Synthia H. Mellon,3 and Keesook Lee1*

Hormone Research Center, School of Biological Sciences and Technology,1 Department of Biology, Chonnam National University, Gwangju 500-757, Republic of Korea,2 Department of Obstetrics and Gynecology, University of California, San Francisco, California 941433

Received 7 August 2003/ Returned for modification 23 September 2003/ Accepted 29 December 2003

Tumor necrosis factor alpha (TNF-{alpha}) has been demonstrated to inhibit steroidogenesis in Leydig cells at the transcriptional level of steroidogenic enzymes. However, the molecular mechanism of this observed gene repression is not well understood. We now demonstrate that nuclear factor {kappa}B (NF-{kappa}B) activated by TNF-{alpha} inhibits the transactivation of orphan nuclear receptors, which regulate the expression of steroidogenic-enzyme genes. TNF-{alpha} treatment suppressed the luteinizing-hormone-induced or Nur77/SF-1-stimulated promoter activity of steroidogenic-enzyme genes in Leydig cells. The TNF-{alpha}-mediated gene suppression was blocked by treatment with an inhibitor of NF-{kappa}B. In addition, overexpression of the p65 (RelA) subunit of NF-{kappa}B showed the same effect as TNF-{alpha} and inhibited Nur77 transactivation, suggesting the involvement of NF-{kappa}B activation in the observed gene repression. Physical association of Nur77 with p65 was revealed by mammalian two-hybrid, GST pull-down, and coimmunoprecipitation analyses. The NF-{kappa}B inhibition of Nur77 transactivation was likely due to the competition of p65 for Nur77 binding with coactivators. Finally, chromatin immunoprecipitation assays revealed that TNF-{alpha} treatment caused the recruitment of NF-{kappa}B to the promoter of the steroidogenic-enzyme P450c17 gene, supporting the hypothesis that the TNF-{alpha}-mediated gene repression involves NF-{kappa}B inhibition of the transcriptional activity of Nur77 and other orphan nuclear receptors. These findings provide a molecular mechanism underlying the inhibition of testicular steroidogenesis by proinflammatory cytokines.

* Corresponding author. Mailing address: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea. Phone: 82-62-530-0509. Fax: 82-62-530-0500. E-mail: klee{at}chonnam.ac.kr.

Molecular and Cellular Biology, April 2004, p. 2593-2604, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2593-2604.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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