CYTOKINE-GUIDED PARACRINE REGULATION OF LEYDIG CELLS

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The long range objectives of this research are to understand the role of testicular interstitial macrophages (TIMs) in the paracrine regulation of Leydig cell steroidogenic function and to elucidate the molecular mechanisms through which TIMs-secreted cytokines regulate steroid hormone biosynthesis. We have determined that immune-activation of mice by injection with bacterial endotoxin, lipopolysaccharide (LPS), results in a marked, but reversible, inhibition of Leydig cell steroidogenesis. Data are presented which demonstrate that LPS stimulates TIMs to express cytokine mRNAs and that cytokines inhibit Leydig cell function in vitro. Together these observations suggest that TIMs might exert a cytokine-guided paracrine regulatory influence on Leydig cell function. The studies proposed in this application will characterize the interaction of TIMs and Leydig cells in situ in control and immune-activated mice by utilizing immunocytochemical and in situ hybridization technologies. These studies will also examine the mechanisms through which cytokines inhibit Leydig cell steroidogenesis utilizing molecular biological and biochemical technologies. The specific aims of this project are: (1) To examine the interaction of TIMs and Leydig cells in situ in control and immune-activated mice; (2) To determine what factors are responsible for the inhibition of Leydig cell steroidogenesis; and (3) To determine the mechanisms through which cytokines inhibit Leydig cell steroidogenesis. Infection and chronic inflammation, conditions associated with increased cytokine production by activated macrophages, often result in impaired male reproductive function. Testosterone production by Leydig cells is essential for spermatogenesis. TIMs and Leydig cells are closely associated in the testis. This suggests that TIMs might exert a cytokine-guided paracrine regulatory influence over Leydig cells. The studies proposed in this application will test the hypothesis that immune-activation of TIMs results in the secretion of cytokines which inhibit Leydig cell steroidogenesis.