Meikle A W, Cardoso de Sousa J C, Dacosta N, Bishop D K, Samlowski W E
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
J Androl. 1992 Sep-Oct;13(5):437-43.
It was recently observed that treatment of patients with a high dosage of human interleukin (IL-2) resulted in suppression of plasma concentrations of testosterone. A murine model was developed to assess the direct and indirect effects of murine IL-2 and the secondarily released cytokines, gamma interferon (INF gamma), and tumor necrosis factor (TNF alpha), on testosterone production in isolated Leydig cells. Pretreatment for 24 hours with IL-2 (100 to 500 IU/ml) or INF gamma (100 to 1000 IU/ml) significantly decreased testosterone production in response to luteinizing hormone (LH; P < 0.02 and 0.005, respectively). The combinations of INF gamma with either TNF alpha or IL-2 produced enhanced suppressive effects on Leydig cell testosterone production. Steroidogenic precursors (22-hydroxycholesterol, 17 alpha-hydroxypregnenolone, and dehydroepiandrosterone) restored testosterone secretion to control levels after preincubation with INF gamma or TNF alpha. In contrast, the inhibition of testosterone synthesis produced by either IL-2 or INF gamma plus TNF alpha could be reversed by 17 alpha-hydroxypregnenolone and dehydroepiandrosterone, but not by 22-hydroxycholesterol (P < 0.01). Dibutyryl cyclic adenosine monophosphate was also ineffective in reversing the inhibitory effects of these cytokines on synthesis. Although IL-2 directly inhibited synthesis in isolated Leydig cells, it stimulated testosterone production (P < 0.005) in minced murine testes. This suggests that IL-2 releases regulatory factors from other cells that were able to overcome the direct inhibitory effect of IL-2. This stimulatory effect was not caused by INF gamma and TNF alpha because INF gamma alone or with TNF alpha inhibited (P < 0.005) testosterone production in minced testes.(ABSTRACT TRUNCATED AT 250 WORDS)
最近观察到，用高剂量的人白细胞介素（IL-2）治疗患者会导致睾酮血浆浓度受到抑制。开发了一种小鼠模型，以评估小鼠IL-2以及继发释放的细胞因子γ干扰素（INFγ）和肿瘤坏死因子（TNFα）对分离的睾丸间质细胞睾酮生成的直接和间接影响。用IL-2（100至500 IU/ml）或INFγ（100至1000 IU/ml）预处理24小时，会显著降低对促黄体生成素（LH）的睾酮生成反应（分别为P < 0.02和0.005）。INFγ与TNFα或IL-2的组合对睾丸间质细胞睾酮生成产生增强的抑制作用。在与INFγ或TNFα预孵育后，类固醇生成前体（22-羟胆固醇、17α-羟孕烯醇酮和脱氢表雄酮）将睾酮分泌恢复到对照水平。相比之下，IL-2或INFγ加TNFα产生的睾酮合成抑制可被17α-羟孕烯醇酮和脱氢表雄酮逆转，但不能被22-羟胆固醇逆转（P < 0.01）。二丁酰环磷酸腺苷在逆转这些细胞因子对合成的抑制作用方面也无效。尽管IL-2直接抑制分离的睾丸间质细胞中的合成，但它刺激切碎的小鼠睾丸中的睾酮生成（P < 0.005）。这表明IL-2从其他细胞释放出能够克服IL-2直接抑制作用的调节因子。这种刺激作用不是由INFγ和TNFα引起的，因为单独的INFγ或与TNFα一起会抑制（P < 0.005）切碎睾丸中的睾酮生成。（摘要截断于250字）
