CREMa suppresses spleen tyrosine kinase expression in normal but not systemic lupus erythematosus T cells

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 receptormediated signaling process, and increased amounts of CREMa, which suppresses the production of interleukin-2. Syk expression can be suppressed by CREMa. This study was undertaken to investigate why CREMa fails to suppress Syk expression in SLE T cells. Methods. CREM alpha was overexpressed in healthy T cells by transfection with CREM alpha 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 CREM alpha -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 CREM alpha binding and histone H3 acetylation. Results. Increased CREM alpha 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 CREM alpha 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 CREM alpha to bind and suppress the expression of Syk, resulting in aberrant T cell signaling.