Open AccessCREMα suppresses spleen tyrosine kinase expression in normal but not systemic lupus erythematosus T cells
Author(s) -
Ghosh Debjani,
KisToth Katalin,
Juang YuangTaung,
Tsokos George C.
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.33375
Subject(s) - syk , chromatin immunoprecipitation , microbiology and biotechnology , zap70 , cancer research , biology , tyrosine kinase , immunology , t cell , gene expression , promoter , signal transduction , interleukin 21 , immune system , gene , biochemistry
Objective T cells from patients with systemic lupus erythematosus (SLE) display increased amounts of spleen tyrosine kinase (Syk), which is involved in the aberrant CD3/T cell receptor–mediated signaling process, and increased amounts of CREMα, which suppresses the production of interleukin‐2. Syk expression can be suppressed by CREMα. This study was undertaken to investigate why CREMα fails to suppress Syk expression in SLE T cells. Methods CREMα was overexpressed in healthy T cells by transfection with CREMα expression vector, and Syk expression and phosphorylation were measured. A newly identified cAMP response element (CRE) site on the SYK promoter was characterized by chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay. The CREMα‐mediated repression of Syk expression was further evaluated by analyzing SYK promoter activity. T cells from SLE patients and healthy individuals were subjected to ChIP to evaluate CREMα binding and histone H3 acetylation. Results Increased CREMα levels suppressed Syk expression by direct binding to a CRE site of the SYK promoter in T cells from healthy individuals but failed to do so in T cells from SLE patients. The failure of CREMα to suppress Syk expression in SLE T cells was due to weaker binding to the CRE site of the SYK promoter compared to healthy T cells because the promoter site is hypoacetylated in SLE T cells and therefore of limited access to transcription factors. Conclusion Our findings indicate that epigenetic alteration of the SYK promoter in SLE T cells results in the inability of the transcriptional repressor CREMα to bind and suppress the expression of Syk, resulting in aberrant T cell signaling.