Turnbull A, Rivier C
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, Calif. 92037, USA.
Neuroimmunomodulation. 1995 Jul-Aug;2(4):224-35. doi: 10.1159/000097200.
The immune system and several endocrine axes communicate with each other through a network of molecules which collectively produce a coordinated response to immune challenges. This phenomenon, necessary for the survival of the organism, is thought to involve the release, by activated cells in the periphery, of proteins, called cytokines, which inform the brain about immune activation. The brain then organizes a series of neuroendocrine responses which participate in the regulation of the host response. With regard to the influence of cytokines on the hypothalamic-pituitary-gonadal axis, we know that the injection of these proteins lowers gonadotropin-releasing hormone release, which in turn inhibits luteinizing hormone (LH) secretion. These changes would be expected to decrease sex steroid production and, indeed, estrogens and testosterone are low in female and male rats, respectively, following acute intracerebroventricular (i.c.v.) injection of interleukin (IL)-1 beta. There is, however, another possibility that central cytokines could alter ovarian and testicular function independently of changes in gonadotropin levels. Prolonged i.c.v. infusion of the cytokine into the female rat brain produced a dramatic rise in progesterone levels. The absence of a comparable change in the progesterone release rate of males infused with IL-1 beta, and the presence of marked surges of prolactin (PRL) in the females, suggests that IL-1 beta altered ovarian function, and that the persistence of large corpora lutea induced PRL release. The possibility that the cytokine might stimulate the brain circuits that regulate PRL release, while possible, appears remote, because male rats injected with IL-1 beta showed significantly blunted PRL levels. In intact adult male rats, i.c.v. IL-1 beta administration caused the expected decrease in LH and testosterone levels, but was also accompanied by a loss of testicular responsiveness to gonadotropins. Though elevated levels of corticosteroids are known to interfere with normal gonadal steroidogenesis, blockade of IL-1-induced corticosterone release did not reverse the inhibitory influence of the cytokine. One mechanism that deserves attention is the possibility that i.c.v. injection of IL-1 beta might increase circulating cytokine levels, and indeed plasma IL-6 concentrations were significantly elevated in rats treated with IL-1 beta. This humoral mechanism may disrupt testicular function through the documented inhibitory effects of blood-borne cytokines on Leydig cell function. In addition, brain cytokines might influence a variety of peripheral events through direct (neural?) connections. This brief review discusses the hypothesis that there are brain-to-gonad connections that bypass the pituitary, and presents results that might support the possibility that central injection of IL-1 beta decreases testosterone secretion independently of blunted LH levels.
免疫系统和几个内分泌轴通过一个分子网络相互通信，这些分子共同对免疫挑战产生协调反应。这种对生物体生存至关重要的现象，被认为涉及外周活化细胞释放被称为细胞因子的蛋白质，这些蛋白质将免疫激活的信息传递给大脑。然后大脑组织一系列神经内分泌反应，参与宿主反应的调节。关于细胞因子对下丘脑 - 垂体 - 性腺轴的影响，我们知道注射这些蛋白质会降低促性腺激素释放激素的释放，进而抑制黄体生成素（LH）的分泌。这些变化预计会减少性类固醇的产生，事实上，在急性脑室内（i.c.v.）注射白细胞介素（IL）-1β后，雌性和雄性大鼠体内的雌激素和睾酮水平分别降低。然而，还有另一种可能性，即中枢细胞因子可能独立于促性腺激素水平的变化而改变卵巢和睾丸功能。向雌性大鼠脑内长期i.c.v.注入这种细胞因子会使孕酮水平急剧升高。向雄性大鼠注入IL-1β后其孕酮释放率没有类似变化，而雌性大鼠出现明显的催乳素（PRL）激增，这表明IL-1β改变了卵巢功能，并且大量黄体的持续存在诱导了PRL的释放。细胞因子可能刺激调节PRL释放的脑回路，虽然有这种可能性，但似乎不太可能，因为注射IL-1β的雄性大鼠PRL水平显著降低。在完整的成年雄性大鼠中，i.c.v.给予IL-1β导致LH和睾酮水平如预期那样降低，但同时睾丸对促性腺激素的反应性也丧失了。虽然已知皮质类固醇水平升高会干扰正常的性腺类固醇生成，但阻断IL-1诱导的皮质酮释放并不能逆转细胞因子的抑制作用。一个值得关注的机制是i.c.v.注射IL-1β可能会增加循环中的细胞因子水平，事实上，用IL-1β处理的大鼠血浆IL-6浓度显著升高。这种体液机制可能通过血液中细胞因子对睾丸间质细胞功能的抑制作用来破坏睾丸功能。此外，脑内细胞因子可能通过直接（神经？）连接影响各种外周事件。这篇简短的综述讨论了存在绕过垂体的脑 - 性腺连接的假说，并展示了可能支持中枢注射IL-1β独立于LH水平降低而减少睾酮分泌这一可能性的结果。
