Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing
Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing
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DOI：
10.1172/jci11182
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发表时间：
2000-12-01
影响因子：
15.9
通讯作者：
Melmed, S
中科院分区：
文献类型：
--
作者：
Bousquet, C;Zatelli, MC;Melmed, S
神经内分泌促肾上腺皮质激素分泌响应外周炎症和应激信号。我们以前证明，促炎细胞因子，白血病抑制因子（LIF），影响下丘脑-垂体-肾上腺轴（HPA）通过刺激在体外和体内垂体阿黑皮素原（POMC）基因表达和ACTH分泌，并通过增强下丘脑促肾上腺皮质激素释放激素（CRH）的作用。尽管迄今为止所显示的调节POIR-IC表达的途径仅涉及cAMP或钙，但我们在此描述了LIF对POMC转录的直接和间接STAT 3依赖性调节。使用POMC启动子的渐进5 '缺失，我们鉴定了一个LIF响应性-407/-301区域，该区域包含与STAT 3 DNA结合基序相关的-399/-379内的两个并列序列。-399/-379内的每个序列分别对应于STAT 3的低亲和力和直接结合位点，但是组合时，这些序列协同地以高亲和力结合STAT 3。此外，LIF激活的STAT 3通过诱导和增强CRH诱导的c-fos和JunB表达以及与POMC AP-1元件结合来间接介导LIF促肾上腺皮质激素作用。因此，我们得出结论，直接和间接途径介导LIF诱导的STAT 3激活POMC转录。POMC基因的STAT 3依赖性调节的证明代表了免疫-神经内分泌接口的强大机制，并意味着炎症和应激源性STAT 3诱导细胞因子直接刺激ACTH分泌。
Neuroendocrine ACTH secretion responds to peripheral inflammatory and stress signals. We previously demonstrated that the proinflammatory cytokine, leukemia inhibitory factor (LIF), affects the hypothalamo-pituitary-adrenal axis (HPA) by stimulating in vitro and in vivo pituitary proopiomelanocortin (POMC) gene expression and ACTH secretion and by potentiating the action of hypothalamic corticotropin releasing hormone (CRH). Whereas pathways shown thus far to regulate POIR-IC expression exclusively involve cAMP or calcium, we here describe a direct and indirect STAT3-dependent regulation of POMC transcription by LIF. Using progressive 5'-deletions of POMC promoter, we identified a LIF-responsive -407/-301 region that contains two juxtaposed sequences within -399/-379 related to a STAT3 DNA-binding motif. Each sequence within -399/-379 separately corresponds to a low-affinity and direct binding site for STAT3, but, in combination, these sequences bind STAT3 cooperatively and with high affinity. Moreover, LIF-activated STAT3 indirectly mediates LIF corticotroph action by inducing and potentiating CRH-induced c-fos and JunB expression and binding to the POMC AP-1 element. We therefore conclude that both a direct and indirect route mediate LIF-induced STAT3 activation of POMC transcription. Demonstration of STAT3-dependent regulation of the POMC gene represents a powerful mechanism for immuno-neuroendocrine interfacing and implies a direct stimulation of ACTH secretion by inflammatory and stress-derived STAT3-inducing cytokines.