CYTOKINE-GUIDED PARACRINE REGULATION OF LEYDIG CELLS

这项研究的长期目标是了解 睾丸间质巨噬细胞在旁分泌调节中的作用 间质细胞类固醇合成功能及分子机制的研究 TIMS分泌的细胞因子调节类固醇激素的机制 生物合成。 我们已经测定了注射阿司匹林对小鼠的免疫激活作用。 细菌内毒素，脂多糖(LPS)，导致显著的，但 可逆性，抑制间质细胞类固醇合成。数据是 证明了内毒素刺激TIMs表达细胞因子 MRNAs和细胞因子在体外抑制间质细胞的功能。同舟共济 这些观察表明，TIMs可能在细胞因子的引导下发挥作用 旁分泌调节对间质细胞功能的影响。这些研究 本申请中提出的将描述TIM之间的相互作用 在对照组和免疫激活的小鼠中原位和间质细胞 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通过哪些机制 利用分子生物学和分子生物学技术抑制间质细胞类固醇合成 生化技术。本项目的具体目标是：(1) 对照中原位检测TIMs与间质细胞的相互作用 和免疫激活的小鼠；(2)确定哪些因素对 抑制间质细胞类固醇合成；及(3)测定 细胞因子抑制间质细胞的机制 类固醇合成。 感染和慢性炎症，与增加相关的条件 由激活的巨噬细胞产生的细胞因子，通常会导致 男性生殖功能。间质细胞产生的睾酮是 对于精子发生来说是必不可少的。TIMs和Leydig细胞关系密切 与睾丸相关。这表明TIMS可能会发挥一种 细胞因子引导的旁分泌调节对间质细胞的影响。这个 本申请中提出的研究将检验这一假设 TIMs的免疫激活会导致细胞因子的分泌，从而 抑制间质细胞类固醇合成。

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.