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Title: Intratesticular delivery of tumor necrosis factor-alpha and ceramide directly abrogates steroidogenic acute regulatory protein expression and Leydig cell steroidogenesis in adult rats
Authors: Morales, Victoria
Santana, Pino
Díaz, Raquel
Tabraue, Carlos 
Gallardo, Germán 
López Blanco, Félix 
Hernández, Inmaculada
Fanjul Rodríguez, Luisa Fernanda 
Ruiz De Galarreta, Carlos M.
UNESCO Clasification: 230221 Biología molecular
2403 Bioquímica
320502 Endocrinología
Keywords: Cultured Granulosa-Cells
Levels In-Vivo
Testicular Macrophages
Injected Interleukin-1-Beta
Proinflammatory Cytokines, et al
Issue Date: 2003
Journal: Endocrinology (Philadelphia) 
Abstract: Systemic or intratesticular release of TNFα and IL1β 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 TNFα and IL1β 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 TNFα 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 TNFα 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 IL1β 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 TNFα 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.
ISSN: 0013-7227
DOI: 10.1210/en.2003-0569
Source: Endocrinology, [ISSN 0013-7227], v. 144 (11), p. 4763-4772
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