CREMα 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 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.