Calcium/calmodulin-dependent protein kinase II regulates IL-10 production by human T lymphocytes: A distinct target in the calcium dependent pathway

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• 作者：Stavroula Boubali^a ; ¹ ; Kassiani Liopeta^a ; ¹ ; Laura Virgilio^b ; George Thyphronitis^c ; George Mavrothalassitis^b ; George Dimitracopoulos^a ; Fotini Paliogianni^a ; ^{fpal@upatras.gr}
• 关键词：Ca2+ ; calcium ; CaM ; calmodulin ; CaMK ; Ca2+/calmodulin-dependent protein kinases ; CaMKII ; Ca2+/calmodulin-dependent protein kinase II ; CaMKIV ; Ca2+/calmodulin-dependent protein kinase IV ; HDACs ; histone deacetylases ; I ; Ionomycin ; I/PMA ; Ionomycin/PMA ; MEF
• 刊名：Molecular Immunology
• 出版年：2012
• 期刊代码：112_01615890
• 类别：bio
• 出版时间：September, 2012
• 卷：52
• 期：2
• 页码：51-60
• 文件大小：818 K

摘要

Calcium (Ca²⁺) plays an essential role in lymphocyte activation and differentiation by affecting signaling pathways leading to cytokine production. Among the enzymes responding to calcium increase, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) has been involved in anergy with a still poorly characterized role. IL-10 produced by different T lymphocyte subpopulations is critical mediator of tolerance. We tested the hypothesis that CaMKII may be involved in IL-10 production. We report that CaMKII upregulates IL-10 production by primary human T lymphocytes stimulated through the antigen receptor or bypassing that. Overexpression of constitutively active mutant forms of Calcineurin or CaMKII specifically increase IL-10 protein product and IL-10 mRNA accumulation in T lymphocytes. By cotransfecting constitutively active CaMKII with luciferase reporter plasmids carrying specific fragments or the whole IL-10 promoter, we show that CaMKII specifically activates IL-10 promoter activity, whereas it inhibits IL-2 and IL-4 promoter. This effect is mediated by the first 500 bp fragment, which contains binding sites for Myocyte Enhancer Factor-2 (MEF2). A constitutively active mutant of CaMKII activated a luciferase reporter plasmid under the control of MEF2, when cotransfected in T lymphocytes stimulated by Ionomycin and PMA, whereas its inhibitor KN-62 inhibited MEF2 binding in cell lysates of the same cells. Moreover, overexpression of MEF2 enhanced by 2.5-fold IL-10 promoter activity. Our data for the first time suggest a distinct role of CaMKII in the induction of anergy in T lymphocytes, by differential regulation of IL-10 and IL-2 gene transcription suggest MEF2 as a molecular target which can integrate different calcium signals.