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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Increased binding of CREM to the –180 site of the IL-2 promoter in SLE T...
Increased binding of CREM to the –180 site of the IL-2 promoter in SLE T cells. (A) Nuclear proteins were incubated with a 32P-labeled oligonucleotide encoding the –180 site of the IL-2 promoter as described in Methods. Shown are 3 independently conducted EMSAs, each containing 1 pair of simultaneously purified normal (N) and SLE T cells. (B) Nuclear proteins from an SLE patient were incubated with the –180 oligonucleotide with or without antibody against CREB, CREM, or c-Jun for 15 minutes, followed by shift analysis. (C) Nuclear proteins from primary T cells were incubated with 32P-labeled oligonucleotide encoding the –180 site of the IL-2 promoter. Where indicated, unlabeled wild-type or mutant oligonucleotides containing 2 mutated nucleotides were also added into the reaction.