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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Figure 13

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The TCR/CD3 complex represents the ligand for SLE serum IgG that is resp...
The TCR/CD3 complex represents the ligand for SLE serum IgG that is responsible for the increased expression of –180/protein complex formation. (A) Wild-type Jurkat T cells or J.EMS.T3.3 cells (a Jurkat T cell subline missing the TCR/CD3 complex) were treated with 1% normal or SLE sera for 3 hours, and nuclear extracts were subjected to a shift assay using the –180 oligonucleotide. (B) Cumulative data (n = 4) are shown. The y axis indicates relative densitometric units with the effect on TCR/CD3–positive cells set at 1. *P < 0.05. (C) Normal or SLE sera were adsorbed for 30 minutes at room temperature and another 30 minutes at 4–C on either Jurkat or J.EMS.T3.3 T cells and used to treat normal T cells for 3 hours. Nuclear extracts were subjected to a shift assay using the –180 oligonucleotide. (D) Cumulative data showing the effect of adsorption of SLE sera (n = 4) on TCR/CD3–positive and –negative Jurkat T cells. The y axis indicates relative densitometric units with the effect of sera adsorbed on TCR/CD3–positive cells set at 1. *P < 0.05. (E) SLE sera were adsorbed on TCR/CD3–positive and –negative cells, and the IgG fraction was isolated and used to treat normal T cells for 3 hours. Nuclear extracts were isolated and subjected to a shift assay using the –180 oligonucleotide. One of 2 similar experiments is shown.