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J. Biol. Chem., Vol. 282, Issue 8, 5420-5431, February 23, 2007

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Transcriptional Regulation of FasL Expression and Participation of sTNF- in Response to Sertoli Cell Injury^*

Pei-Li Yao, Yi-Chen Lin, Pragati Sawhney, and John H. Richburg¹

From the Institute for Cellular and Molecular Biology and the Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin, Texas 78712-1074

The Fas/FasL signaling pathway has previously been demonstrated to be critical for triggering germ cell apoptosis in response to mono-(2-ethylhexyl)phthalate (MEHP)-induced Sertoli cell injury. Although Sertoli cells ubiquitously express the FasL protein, MEHP-induced germ cell apoptosis appears to tightly correlate with increased levels of Sertoli cell FasL. Here we characterize the transcriptional regulation of the murine FasL gene in Sertoli cells after MEHP exposure. A serial deletion strategy for 1.5 kb of the 5'-upstream activating sequence of the FasL promoter was used to determine transcriptional activity in response to MEHP. Luciferase activity of the FasL promoter in the rat Sertoli cell line ASC-17D revealed that two regions, -500 to -324 and -1250 to -1000, were necessary to drive the inducible transcription of FasL. Sequence analysis of these two regions revealed two cis-regulatory elements, NF-B and Sp-1. By site-directed mutagenesis, electrophoretic mobility shift and chromatin immunoprecipitation assays, it was confirmed that MEHP-induced FasL expression is enhanced through the transcriptional regulation of both NF-B and Sp-1. Experiments performed both in vitro and in vivo revealed that MEHP exposure results in an increased production of sTNF- and that sTNF--mediated NF-B activation causes robust increases in FasL levels in both the ASC-17D Sertoli cell line and in primary rat Sertoli cell/germ cell co-cultures. In the seminiferous epithelium, Sertoli cells express TNFR1, whereas germ cells produce TNF-. Therefore, sTNF- released by germ cells after MEHP-induced Sertoli cell injury acts upon Sertoli cell TNFR1 and activates NF-B and Sp-1 that consequently causes a robust induction of FasL expression. These novel findings point to a potential "feed-forward" signaling mechanism by which germ cells prompt Sertoli cells to trigger their apoptotic elimination.

Received for publication, September 25, 2006 , and in revised form, December 4, 2006.

^* This work was supported by NIEHS National Institutes of Health Grant ES09145 (to J. H. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1 University Station, Austin, TX. 78712-1074. Tel.: 512-471-4736; Fax: 512-471-5002; E-mail: john_richburg{at}mail.utexas.edu.

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