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Intratesticular Delivery of Tumor Necrosis Factor- and Ceramide Directly Abrogates Steroidogenic Acute Regulatory Protein Expression and Leydig Cell Steroidogenesis in Adult Rats

Departamento de Bioquímica, Biología Molecular y Fisiología. Facultad de Medicina, Universidad de Las Palmas de Gran Canaria, Las Palmas 35016, Spain

Address all correspondence and requests for reprints to: Carlos M. Ruiz de Galarreta, Department of Biochemistry, Molecular Biology, and Physiology, University of Las Palmas, School of Medicine, Las Palmas de GC 35061, Spain. E-mail: cruiz{at}dbbf.ulpgc.es.

Systemic or intratesticular release of TNF and IL1ß have been implicated in the reduced testosterone biosynthesis and impaired production of competent spermatozoa found in human patients suffering from sepsis or chronic inflammation. Although in vitro and in vivo studies have demonstrated that TNF and IL1ß intercept the hypothalamic-pituitary testis axis at different levels, the site(s) of action and relative contribution of each cytokine to the overall testicular failure associated to systemic inflammatory processes remains poorly defined. In this study we show that intratesticular delivery of TNF induced a rapid (4 h) and sustained (up to 24 h) reduction in steroidogenic acute regulatory (StAR) protein expression and testosterone biosynthesis in nonstimulated or human chorionic gonadotropin-treated intact or hypophysectomized rats. Bilateral treatment with cell-permeant short-chain ceramides (C2-cer or C6-cer) reproduced the early (4 h) inhibitory action of TNF on testosterone biosynthesis and testicular StAR expression. The inhibitory action of C2-cer or C6-cer was not observed in animals treated with inactive analogs (dihydroceramide), phosphorylcholine, sphingosine, or sphoingosine-1P. In sharp contrast to the previously described ability of IL1ß to prevent human chorionic gonadotropin-stimulated Leydig cell steroidogenesis in vitro, serum testosterone and testicular StAR protein expression remained unchanged in animals bilaterally injected with this cytokine. These data support the concept that TNF triggers different effector mechanisms to directly inhibit Leydig cell StAR expression and steroidogenesis, which ultimately contribute to the global reproductive failure associated with chronic inflammation and sepsis.

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