Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A*
Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A*
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DOI：
10.1074/jbc.m111.286492
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发表时间：
2011-12
期刊：
影响因子：
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通讯作者：
I. Rudloff;Malte Bachmann;J. Pfeilschifter;H. Mühl
中科院分区：
文献类型：
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作者：
I. Rudloff;Malte Bachmann;J. Pfeilschifter;H. Mühl
背景：由于白细胞介素-22在自身免疫性炎症中具有致病性，因此通过免疫调节对其进行调节和阻断至关重要。结果：在T细胞模型中，CREB、NF-AT和IKKα支持IL-22启动子激活。最后，通过对NF-AT的作用，环孢菌素损害白细胞介素-22的表达。结论：IL-22是环孢素直接作用于T细胞的靶点。意义：观察结果可能有助于环孢菌素在自身免疫（如银屑病）中的疗效。IL-22是一种免疫调节细胞因子，在自身免疫模型如实验性银屑病中显示病理功能。了解驱动IL-22的分子机制，以及目前免疫抑制药物靶向这一过程的能力，可能会为新的治疗选择开辟一条道路。在这里，我们试图表征人IL 22基因表达的调控，重点是Jurkat T细胞的建立模型。此外，原型免疫抑制剂环孢素A（CsA）的影响进行了研究。我们报道TPA/A23187（T/A）或α CD 3诱导的IL-22可被CsA或相关的FK 506抑制。用外周血单核细胞或纯化的CD 3 + T细胞获得了类似的数据。IL 22启动子分析（−1074至+156 bp）揭示了NF-AT（−95/−91 nt）和CREB（−194/−190 nt）结合位点在基因诱导中的作用。事实上，在T/A的影响下，CREB和NF-ATc 2而不是c-Rel与这些元件的结合可以通过ChIP来证明。由于CsA具有损害IκB激酶（IKK）复合物活化的能力，因此对IKKα/β抑制剂IKKVII进行了评价。IKKVII同样减少Jurkat细胞和外周血单核细胞中的IL-22诱导。有趣的是，用针对IKKα的siRNA转染Jurkat细胞损害了IL 22基因表达。所提供的数据表明，NF-AT、CREB和IKKα有助于快速IL 22基因诱导。特别地，本文检测到的NF-AT的关键作用可以形成CsA对T细胞的IL-22表达的直接作用的基础，这可以有助于药物在自身免疫中的治疗功效。
Background: Because interleukin-22 is pathogenic in autoimmune inflammation its regulation and blockage by immunomodulation is crucial. Results: Interleukin-22 promoter activation in a T cell model is supported by CREB, NF-AT, and IKKα. Largely by action on NF-AT, cyclosporin impairs interleukin-22 expression. Conclusion: Interleukin-22 is a direct cyclosporin target in T cells. Significance: Observations made likely contribute to cyclosporin efficacy in autoimmunity such as psoriasis. IL-22 is an immunoregulatory cytokine displaying pathological functions in models of autoimmunity like experimental psoriasis. Understanding molecular mechanisms driving IL-22, together with knowledge on the capacity of current immunosuppressive drugs to target this process, may open an avenue to novel therapeutic options. Here, we sought to characterize regulation of human IL22 gene expression with focus on the established model of Jurkat T cells. Moreover, effects of the prototypic immunosuppressant cyclosporin A (CsA) were investigated. We report that IL-22 induction by TPA/A23187 (T/A) or αCD3 is inhibited by CsA or related FK506. Similar data were obtained with peripheral blood mononuclear cells or purified CD3+ T cells. IL22 promoter analysis (−1074 to +156 bp) revealed a role of an NF-AT (−95/−91 nt) and a CREB (−194/−190 nt) binding site for gene induction. Indeed, binding of CREB and NF-ATc2, but not c-Rel, under the influence of T/A to those elements could be proven by ChIP. Because CsA has the capability to impair IκB kinase (IKK) complex activation, the IKKα/β inhibitor IKKVII was evaluated. IKKVII likewise reduced IL-22 induction in Jurkat cells and peripheral blood mononuclear cells. Interestingly, transfection of Jurkat cells with siRNA directed against IKKα impaired IL22 gene expression. Data presented suggest that NF-AT, CREB, and IKKα contribute to rapid IL22 gene induction. In particular the crucial role of NF-AT detected herein may form the basis of direct action of CsA on IL-22 expression by T cells, which may contribute to therapeutic efficacy of the drug in autoimmunity.