Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation
Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation
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DOI：
10.1073/pnas.97.16.9317
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发表时间：
2000-08-01
影响因子：
11.1
通讯作者：
Muglia, LJ
中科院分区：
文献类型：
--
作者：
Bethin, KE;Vogt, SK;Muglia, LJ
糖皮质激素在免疫激发后控制细胞因子应答中起关键作用。相反，细胞因子通过下丘脑-垂体-肾上腺轴调节糖皮质激素的产生。为了确定白细胞介素-6（IL-6）增强肾上腺功能的效力和机制，我们利用了促肾上腺皮质激素释放激素（CRH）、IL-6或两者都缺乏的小鼠。缺乏CRH作用的小鼠表现出对心理和代谢挑战的糖皮质激素产生严重受损，但对激活免疫系统的应激源的反应接近正常。在本文中，我们表明，IL-6是必不可少的激活下丘脑-垂体-肾上腺轴在免疫挑战中的情况下，下丘脑：输入CRH。IL-6受体存在于垂体促肾上腺皮质激素细胞和肾上腺皮质细胞上，这与IL-6在增强肾上腺功能中绕过CRH的能力一致。注射细菌脂多糖后，CRH或IL-6缺陷小鼠的血浆皮质酮水平显著低于野生型小鼠，但显著高于CRH和IL-6缺陷小鼠。使用2C 11（一种针对T细胞受体的抗体）的第二种免疫系统激活模型表明，CRH或IL-6缺陷小鼠的皮质酮反应正常，但CRH和IL-6缺陷小鼠的反应明显降低。令人惊讶的是，IL-6对调节肾上腺对应激反应的相对贡献在雌性小鼠中大于雄性小鼠。小鼠中IL-6作用的这种性别特异性差异表明进一步分析IL-6在确定许多人类炎症/自身免疫性疾病中观察到的女性优势方面的效用。
Glucocorticoids play a critical role in control of the cytokine response after immune challenge. Conversely, cytokines modulate glucocorticoid production by the hypothalamic-pituitary-adrenal axis. To define the potency and mechanism of interleukin-6 (IL-6) for augmentation of adrenal function, we exploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorticoid production in response to psychological and metabolic challenge, but near normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothalamic-pituitary-adrenal axis during immunological challenge in the absence of hypothalamic: input from CRH. IL-6 receptors are present on pituitary corticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone levels after bacterial lipopolysaccharide injection in mice deficient in CRH or IL-6 were significantly lower than in wild-type mice but significantly greater than in mice deficient in both CRH and IL-6. A second model of immune system activation using 2C11, an antibody to the T cell receptor, demonstrated a normal corticosterone response in mice deficient in CRH or IL-6, but a markedly decreased response in mice deficient in both CRH and IL-6. Surprisingly, the relative contribution of IL-6 for modulation of the adrenal response to stress is greater in female than in male mice. This gender-specific difference in IL-6 action in mice suggests the utility of further analysis of IL-6 in determining the female predominance seen in many human inflammatory/autoimmune diseases.