Pace Thaddeus W W, Hu Fang, Miller Andrew H
Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, 101 Woodruff Cricle, Suite 4000, Atlanta, GA 30322, USA.
Brain Behav Immun. 2007 Jan;21(1):9-19. doi: 10.1016/j.bbi.2006.08.009. Epub 2006 Oct 27.
Glucocorticoids play an essential role in the response to environmental stressors, serving initially to mobilize bodily responses to challenge and ultimately serving to restrain neuroendocrine and immune reactions. A number of diseases including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids (glucocorticoid resistance), which is believed to be related in part to impaired functioning of the glucocorticoid receptor (GR). Glucocorticoid resistance, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways, which are known to contribute to a variety of diseases as well as behavioral alterations. Recent data indicate that glucocorticoid resistance may be a result of impaired GR function secondary to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress. Indeed, inflammatory cytokines and their signaling pathways including mitogen-activated protein kinases, nuclear factor-kappaB, signal transducers and activators of transcription, and cyclooxygenase have been found to inhibit GR function. Mechanisms include disruption of GR translocation and/or GR-DNA binding through protein-protein interactions of inflammatory mediators with the GR itself or relevant steroid receptor cofactors as well as alterations in GR phosphorylation status. Interestingly, cAMP signal transduction pathways can enhance GR function and inhibit cytokine signaling. Certain antidepressants have similar effects. Thus, further understanding the effects of cytokines on GR signaling and the mechanisms involved may reveal novel therapeutic targets for reversal of glucocorticoid resistance and restoration of glucocorticoid-mediated inhibition of relevant bodily/immune responses during stress and immune challenge.
糖皮质激素在应对环境应激源中发挥着至关重要的作用，最初用于调动身体对挑战的反应，最终用于抑制神经内分泌和免疫反应。包括自身免疫性、感染性和炎症性疾病以及某些神经精神疾病如重度抑郁症在内的多种疾病，都与对糖皮质激素的反应性降低（糖皮质激素抵抗）有关，这被认为部分与糖皮质激素受体（GR）功能受损有关。反过来，糖皮质激素抵抗可能导致过度炎症以及促肾上腺皮质激素释放激素和交感神经系统通路的过度活跃，而这些已知会导致多种疾病以及行为改变。最近的数据表明，糖皮质激素抵抗可能是由于慢性暴露于炎性细胞因子导致GR功能受损所致，如在慢性疾病或慢性应激期间可能发生的那样。事实上，已经发现炎性细胞因子及其信号通路，包括丝裂原活化蛋白激酶、核因子-κB、信号转导和转录激活因子以及环氧化酶，会抑制GR功能。其机制包括通过炎性介质与GR本身或相关类固醇受体辅因子的蛋白质-蛋白质相互作用破坏GR易位和/或GR-DNA结合，以及GR磷酸化状态的改变。有趣的是，cAMP信号转导通路可以增强GR功能并抑制细胞因子信号传导。某些抗抑郁药也有类似作用。因此，进一步了解细胞因子对GR信号传导的影响及其涉及的机制，可能会揭示逆转糖皮质激素抵抗以及在应激和免疫挑战期间恢复糖皮质激素介导的对相关身体/免疫反应抑制的新治疗靶点。
