Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV
Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV
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DOI：
10.1172/jci200522854
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发表时间：
2005-04-01
影响因子：
15.9
通讯作者：
Tsokos, C
中科院分区：
文献类型：
--
作者：
Juang, YT;Wang, Y;Tsokos, C
系统性红斑狼疮(SLE)T细胞高水平表达cAMP反应元件调节剂(CREM)，与IL-2启动子结合，抑制IL-2基因转录。这项研究旨在确定导致SLE T细胞中CREM与IL-2启动子结合增加的途径。研究发现，CaMKIV在SLE T细胞胞核内表达增加，参与CREM的过度表达及其与IL-2启动子的结合。用SLE血清处理正常T细胞后，CREM蛋白表达增加，CREM与IL-2启动子结合增加，IL-2启动子活性和IL-2产生减少。当CaMKIV的主要非活性形式在正常T细胞中表达时，这一过程被取消。SLE血清的作用存在于Ig G组分内，特异性地归因于抗TCR/CD3自身抗体。本研究证实CaMKIV与SLE T细胞CREM表达增加和IL-2产生减少有关，并证明SLE血清中存在抗TCR/CD3抗体可解释CREM表达增加和IL-2产生抑制。
Systemic lupus erythematosus (SLE) T cells express high levels of cAMP response element modulator (CREM) that binds to the IL-2 promoter and represses the transcription of the IL-2 gene. This study was designed to identify pathways that lead to increased binding of CREM to the IL-2 promoter in SLE T cells. Ca2+/calmodulin-dependent kinase IV (CaMKIV) was found to be increased in the nucleus of SLE T cells and to be involved in the overexpression of CREM and its binding to the IL-2 promoter. Treatment of normal T cells with SLE serum resulted in increased expression of CREM protein, increased binding of CREM to the IL-2 promoter, and decreased IL-2 promoter activity and IL-2 production. This process was abolished when a dominant inactive form of CaMKIV was expressed in normal T cells. The effect of SLE serum resided within the IgG fraction and was specifically attributed to anti-TCR/CD3 autoandbodies. This study identifies CaMKIV as being responsible for the increased expression of CREM and the decreased production of IL-2 in SLE T cells and demonstrates that anti-TCR/CD3 antibodies present in SLE sera can account for the increased expression of CREM and the suppression of IL-2 production.