Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV
Yuang-Taung Juang, … , Vasileios C. Kyttaris, George C. Tsokos
Yuang-Taung Juang, … , Vasileios C. Kyttaris, George C. Tsokos
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):996-1005. https://doi.org/10.1172/JCI22854.
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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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SLE serum IgG promotes the binding of protein to the –180 site of the IL...
SLE serum IgG promotes the binding of protein to the –180 site of the IL-2 promoter and decreases the production of IL-2 in normal T cells. (A) SLE and normal sera were fractionated (see Methods) and subjected to electrophoresis. (B) Exposure of normal T cells to SLE sera and IgG fractions (2 μg/ml) from SLE sera increases the formation of –180/protein complex. Data from 1 experiment (n = 4) are shown. (C) SLE sera and IgG fractions of SLE sera (n = 4) limit the ability of normal T cells to produce IL-2. IL-2 production in the presence of normal sample was set at 1 (gray bars).