Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV.
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. Ca(2+)/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.
Juang
Yuang-Taung
YT
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
Wang
Ying
Y
Solomou
Elena E
EE
Li
Yansong
Y
Mawrin
Christian
C
Tenbrock
Klaus
K
Kyttaris
Vasileios C
VC
Tsokos
George C
GC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007376:Interleukin-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D017871:Calcium-Calmodulin-Dependent Protein Kinases