Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV
Yuang-Taung Juang, Ying Wang, Elena E. Solomou, Yansong Li, Christian Mawrin, Klaus Tenbrock, Vasileios C. Kyttaris, George C. Tsokos
Yuang-Taung Juang, Ying Wang, Elena E. Solomou, Yansong Li, Christian Mawrin, Klaus Tenbrock, Vasileios C. Kyttaris, George C. Tsokos
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Article Autoimmunity

Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV

Abstract

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 autoantibodies. 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.

Authors

Yuang-Taung Juang, Ying Wang, Elena E. Solomou, Yansong Li, Christian Mawrin, Klaus Tenbrock, Vasileios C. Kyttaris, George C. Tsokos

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Overexpression of CaMKIV(i), but not overexpression of CaMKII(i), abolis...
Overexpression of CaMKIV(i), but not overexpression of CaMKII(i), abolishes the SLE serum–induced –180 site/protein complex formation. (A) Normal T cells were transfected with control plasmid or plasmids encoding catalytically inactive CaMKII or CaMKIV [CaMKII(i) or CaMKIV(i)]. Three hours later, cells were treated with SLE, RA, or normal sera for 2 more hours and then harvested for EMSA analysis. (B) Cumulative data from 5 experiments are presented. (C) CaMKII(i) does not abolish the effect of SLE serum on the formation of the –180/protein complex. (D) Cumulative data are presented. *P < 0.05.