Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor
Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor
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DOI：
10.1002/hep.24655
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发表时间：
2012-01-01
期刊：
影响因子：
13.5
通讯作者：
Schaper, Fred
中科院分区：
文献类型：
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作者：
Dittrich, Anna;Khouri, Christina;Schaper, Fred
已知糖皮质激素是有效的炎症调节剂，并且已经被用于治疗炎症、免疫和淋巴增生性疾病超过50年。由于它们可能的和有据可查的副作用，详细了解糖皮质激素作用的分子机制和靶点至关重要。已经讨论了几种作用模式;然而，没有一种能完全解释糖皮质激素的所有功能。因此，我们分析了肝脏中糖皮质激素和白细胞介素-6（IL-6）之间的串扰。IL-6具有促炎和抗炎特性，是急性期反应的主要诱导物。IL-6的促炎和抗炎活性之间的平衡受到细胞因子信号传导抑制因子3（SOCS 3）的严格调节，SOCS 3是众所周知的IL-6信号传导的反馈抑制剂。在这里，它表明，糖皮质激素增强IL-6依赖？纤维蛋白原表达。对潜在机制的研究揭示了SOCS 3蛋白表达下调引起的信号转导子和转录激活子3（STAT 3）的激活延长。因此，在SOCS 3缺陷细胞中，糖皮质激素不影响IL-6诱导的信号转导。此外，在gp 130内缺乏SOCS 3募集基序的肝细胞中，IL-6依赖性？纤维蛋白原表达不受糖皮质激素治疗的影响。总结：糖皮质激素干扰IL-6诱导的反馈抑制剂SOCS 3的表达，从而导致肝细胞中急性期基因的表达增强。这一机制有助于解释糖皮质激素如何影响炎症和急性期基因诱导。（肝脏学2012;55：256266）
Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well-documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross-talk between glucocorticoids and interleukin-6 (IL-6) in the liver. IL-6 exerts pro-inflammatory as well as anti-inflammatory properties and is a main inducer of the acute-phase response. The balance between the proinflammatory and anti-inflammatory activities of IL-6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well-known feedback inhibitor of IL-6 signaling. Here, it is demonstrated that glucocorticoids enhance IL-6dependent ?-fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down-regulation of SOCS3 protein expression. Consequently, in SOCS3-deficient cells glucocorticoids do not affect IL-6induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL-6dependent ?-fibrinogen expression is not influenced by glucocorticoid treatment. Conclusion: Glucocorticoids interfere with IL-6induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute-phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute-phase gene induction. (HEPATOLOGY 2012;55:256266)