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 sera stimulate the expression of CREM and its binding to the –180 el...
SLE sera stimulate the expression of CREM and its binding to the –180 element of IL-2 promoter. (A) SLE sera induce CREM mRNA. Normal T cells were stimulated with normal, RA, or SLE sera for 2 hours before RNA was analyzed for the expression level of CREM and actin. (B) Cumulative analysis of the effect of SLE sera on the expression of CREM mRNA. The y axis represents the ratio between the mRNA expression levels of CREM and those of actin in normal T cells treated with SLE, RA, or normal serum. (C) SLE sera induce the expression of CREM in the nucleus. Normal T cells were cultured for 2 hours in RPMI containing 1% serum from normal, RA, or SLE patients. Nuclear proteins were harvested and assayed using Western blotting with the indicated antibodies. Shown are 2 representative Western blots, each containing simultaneously purified nuclear proteins from normal T cells treated with normal, RA, or SLE serum. (D) Cumulative effect of SLE sera on the expression of nuclear CREM protein in normal T cells. The y axis represents the ratio of the expression levels of CREM to those of CREB protein in normal T cells treated with normal, RA, or SLE sera. (E) Increased formation of –180 complex in normal T cells treated with SLE sera. Nuclear proteins from normal T cells treated with sera from normal, RA, or SLE patients were analyzed by EMSA to measure their binding activity to oligonucleotides encoding the –180 element. (F) The y axis represents the –180/protein complex intensity in the T cells treated with SLE, RA, or normal serum. *P < 0.05.