外周白细胞介素-1β抑制雌性小鼠弓状核 kiss1 细胞和 LH 脉冲。
Peripheral interleukin-1β inhibits arcuate kiss1 cells and LH pulses in female mice.
机构信息
Animal Care Program, University of California, San Diego, La Jolla, California, USA.
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Diego, La Jolla, California, USA.
出版信息
J Endocrinol. 2020 Aug;246(2):149-160. doi: 10.1530/JOE-20-0165.
Peripheral immune/inflammatory challenges rapidly disrupt reproductive neuroendocrine function. This inhibition is considered to be centrally mediated via suppression of gonadotropin-releasing hormone secretion, yet the neural pathway(s) for this effect remains unclear. We tested the hypothesis that interleukin-1β inhibits pulsatile luteinizing hormone secretion in female mice via inhibition of arcuate kisspeptin cell activation, a population of neurons considered to be the gonadotropin-releasing hormone pulse generator. In the first experiment, we determined that the inhibitory effect of peripheral interleukin-1β on luteinizing hormone secretion was enhanced by estradiol. We next utilized serial sampling and showed that interleukin-1β reduced the frequency of luteinizing hormone pulses in ovariectomized female mice treated with estradiol. The interleukin-1β-induced suppression of pulse frequency was associated with reduced kisspeptin cell activation, as determined by c-Fos coexpression, but not as a result of impaired responsiveness to kisspeptin challenge. Together, these data suggest an inhibitory action of interleukin-1β upstream of kisspeptin receptor activation. We next tested the hypothesis that estradiol enhances the activation of brainstem nuclei responding to interleukin-1β. We determined that the expression of interleukin-1 receptor was elevated within the brainstem following estradiol. Interleukin-1β induced c-Fos in the area postrema, ventrolateral medulla, and nucleus of the solitary tract; however, the response was not increased by estradiol. Collectively, these data support a neural mechanism whereby peripheral immune/inflammatory stress impairs reproductive neuroendocrine function via inhibition of kisspeptin cell activation and reduced pulsatile luteinizing hormone secretion. Furthermore, these findings implicate the influence of estradiol on peripherally mediated neural pathways such as those activated by peripheral cytokines.
外周免疫/炎症挑战会迅速破坏生殖神经内分泌功能。这种抑制被认为是通过抑制促性腺激素释放激素的分泌来实现的，但这种作用的神经通路尚不清楚。我们假设白细胞介素-1β通过抑制弓状核 kisspeptin 细胞的激活来抑制雌性小鼠的促黄体生成素脉冲分泌，而 kisspeptin 细胞被认为是促性腺激素释放激素脉冲发生器的神经元群体。在第一个实验中，我们确定外周白细胞介素-1β对黄体生成素分泌的抑制作用在雌激素存在下增强。我们接下来利用连续采样显示，白细胞介素-1β降低了用雌激素处理的去卵巢雌性小鼠的黄体生成素脉冲频率。白细胞介素-1β诱导的脉冲频率降低与 kisspeptin 细胞激活减少有关，如 c-Fos 共表达所确定的，但不是由于对 kisspeptin 挑战的反应性受损所致。总之，这些数据表明白细胞介素-1β对 kisspeptin 受体激活具有抑制作用。我们接下来测试了雌激素增强对白细胞介素-1β反应的脑干核激活的假设。我们确定雌激素治疗后，脑干内的白细胞介素-1 受体表达升高。白细胞介素-1β诱导了孤束核、腹外侧延髓和孤束核中的 c-Fos；然而，这种反应并没有被雌激素增强。总的来说，这些数据支持这样一种神经机制，即外周免疫/炎症应激通过抑制 kisspeptin 细胞的激活和减少促黄体生成素的脉冲分泌来损害生殖神经内分泌功能。此外，这些发现表明雌激素对外周介导的神经通路的影响，如外周细胞因子激活的神经通路。
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