CYTOKINE-GUIDED PARACRINE REGULATION OF LEYDIG CELLS

本研究的长期目标是了解 睾丸间质巨噬细胞（TIM）的旁分泌调节 Leydig细胞类固醇生成功能的研究，并阐明 TIMs分泌的细胞因子调节类固醇激素的机制 生物合成 我们已经确定，通过注射 细菌内毒素，脂多糖（LPS），导致一个显着的，但 可逆的，抑制Leydig细胞类固醇生成。 数据 显示LPS刺激TIM表达细胞因子， mRNA和细胞因子在体外抑制Leydig细胞功能。 一起 这些观察结果表明，TIM可能会发挥一种神经递质引导的 旁分泌对间质细胞功能的调节作用。 研究 本申请中提出的方法将表征TIM的相互作用 和Leydig细胞原位在对照组和免疫激活的小鼠， 利用免疫细胞化学和原位杂交技术。 这些研究还将检查细胞因子 利用分子生物学方法抑制Leydig细胞类固醇生成， 生物化学技术 该项目的具体目标是：（1） 在对照组中原位检测TIM和Leydig细胞的相互作用 和免疫激活小鼠;（2）确定哪些因素是负责 用于抑制Leydig细胞类固醇生成;和（3）确定 细胞因子抑制Leydig细胞的机制 类固醇生成 感染和慢性炎症，与增加的 由活化的巨噬细胞产生的细胞因子，通常导致受损的 男性生殖功能 睾丸间质细胞产生睾酮是 对精子生成至关重要。 TIM和Leydig细胞密切相关， 与睾丸有关。 这表明TIM可能会发挥作用， 尼古丁引导的旁分泌调节对间质细胞的影响。 的 在本申请中提出的研究将检验假设， TIM的免疫激活导致细胞因子的分泌， 抑制Leydig细胞类固醇生成。

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.