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TNF Down-Regulates the Fas Ligand and Inhibits Germ Cell Apoptosis in the Human Testis

Program for Developmental and Reproductive Biology, Biomedicum Helsinki, and Hospital for Children and Adolescents, University of Helsinki (V.P., K.E., L.S., M.O., L.D.), FIN-00290 Helsinki, Finland; Wihuri Research Institute (M.O.P.), FIN-00140 Helsinki, Finland; and Department of Anatomy, University of Turku (M.P.), FIN-20520 Turku, Finland

Address all correspondence and requests for reprints to: Virve Pentikäinen, M.D., Hospital for Children and Adolescents, University of Helsinki, P.O. Box 281, FIN-00029 HUS, Helsinki, Finland. E-mail: virve.pentikainen{at}hus.fi

Abstract

The cytokine TNF is known to be secreted by testicular germ cells. However, its effect on maturing germ cells is unknown, and its role in the regulation of spermatogenesis is unclear. Here we aimed at characterizing the effects of TNF on germ cell survival in the human testis. We found that TNF effectively and dose-dependently inhibited germ cell apoptosis, which was induced in vitro by incubating segments of human seminiferous tubules under serum-free culture conditions. EMSAs indicated increased activity of nuclear factor B in seminiferous tubules cultured under apoptosis-inducing conditions. However, we did not observe any significant effect of TNF on the activation of this transcription factor, which is often considered to be a mediator of TNF-induced survival signals. As the expression of the TNF receptor protein in the human seminiferous epithelium was predominantly found in the Sertoli cells, the antiapoptotic effect of TNF is probably mediated via these somatic cells. Interestingly, expression of the Fas ligand, a known inductor of testicular apoptosis, was down-regulated by TNF. Thus, in the seminiferous tubules, germ cell-derived TNF may regulate the level of the Fas ligand and thereby control physiological germ cell apoptosis.

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