Peripheral interleukin-1β inhibits arcuate kiss1 cells and LH pulses in female mice.
2020
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 a result of impaired responsiveness to kisspeptin challenge. Together, these data suggest an inhibitory action of interleukin-1β on or upstream of kisspeptin signaling. We next tested the hypothesis that estradiol enhances activation of brainstem nuclei responding to interleukin-1β. We determined that expression of interleukin-1 receptor was elevated within the brainstem following estradiol. Although interleukin-1β induced c-Fos in the area postrema, ventrolateral medulla, and nucleus of the solitary tract, 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.
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