PDF(Pubmed)
Abstract：
It has been previously shown that the cytokine interleukin 33 is required for two processes, i.e., autophagic digestion of granulosa cells and recruitment of macrophages into atretic follicles, for full disposal of atretic follicles. Now, this study shows that activation of interleukin 33-suppression of tumorigenicity 2-Nuclear Factor ĸB (NFκB) axis in granulosa in early atretic follicles may regulate those two events. Injection of human chorionic gonadotropin has been shown to induce a transient peak of interleukin 33 expression with synchronized atresia. In this model, interleukin 33-independent expression of suppression of tumorigenicity 2 in granulosa cells was detected in early atretic follicles before macrophage invasion. The activation of NFκB pathway in ovaries was further demonstrated in vivo in Tg mice with luciferase-reporter for NFκB activation; the activation was microscopically localized to granulosa cells in early atretic follicles. Importantly, antibody blockage of interleukin 33 or interleukin 33 Knock-out (KO) (Il33-/-) not only inhibited NFκB activity in ovaries, but it also altered expression of two key genes, i.e., reduction in proinflammatory interleukin6 (IL6) expression, and a surge of potential autophagy-inhibitory mammalian target of rapamycin (mTOR) expression in atretic follicles. By contrast, apoptosis and other genes, such as interleukin1β (IL1β) were not affected. In conclusion, in parallel to apoptosis, atresia signals also trigger activation of the interleukin 33-suppression of tumorigenicity 2-NFκB pathway in granulosa, which leads to (1) down-regulated expression of mTOR that is a negative regulator of autophagy and (2) up-regulated expression of proinflammatory IL6.
摘要：
以前已经表明，细胞因子白细胞介素33（IL33）是两个过程所必需的，即颗粒细胞的自噬消化和巨噬细胞募集进入闭锁卵泡，用于充分处理闭锁卵泡。现在,这项研究表明，早期闭锁卵泡颗粒中IL33-ST2（IL33受体）-NFκB轴的激活可能调节这两个事件。已显示注射hCG可诱导IL33表达的瞬时峰值，并伴有同步闭锁。在这个模型中,在巨噬细胞入侵之前，在早期闭锁卵泡中检测到ST2在颗粒细胞中的IL33非依赖性表达。在具有荧光素酶-报道基因的Tg小鼠中，体内进一步证明了卵巢中NFκB途径的激活。在显微镜下，激活定位于早期闭锁卵泡的颗粒细胞。重要的是,IL33或IL33KO（Il33-/-）的抗体阻断不仅抑制卵巢中的NFκB活性，但也改变了两个关键基因的表达，即减少促炎性IL6表达，以及闭锁卵泡中潜在的自噬抑制性mTOR表达激增。相比之下,细胞凋亡和其他基因如IL1β不受影响。总之,与凋亡平行，闭锁信号还触发颗粒中IL33-ST2-NFκB通路的激活，这导致（1）mTOR的表达下调，mTOR是自噬的负调节因子，和(2)促炎性IL6的表达上调。
