Estrogen upregulates cyclic AMP response element modulator alpha expression and downregulates interleukin-2 production by human T lymphocytes (167.8)

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex multifactorial etiopathogenesis and primarily afflicts women. T lymphocytes play a critical role in disease pathogenesis and display abnormal gene expression and function. A major defect is their inability to produce the vital cytokine interleukin-2 (IL-2) due to defects in IL2 transcription. We previously showed that the expression of the transcriptional repressor cyclic AMP response element modulator alpha (CREMα) is increased in SLE T cells, and contributes to reduced IL-2 production. While estrogen is implicated in the onset and exacerbation of SLE, the precise nature of molecular events regulated by estrogen in immune cell function is not well understood. Here we asked whether estrogen regulates the expression of CREMα in human T lymphocytes. We show that exposure of human T cells to 17- β-estradiol leads to increased CREMα mRNA expression, and this increase appears to be estrogen receptor dependent. We show that the increased expression of CREMα is due to increased transcriptional activity of the CREM promoter, and is mediated by increased expression and binding of the Sp1 transcriptional activator. We further show that estrogen treatment leads to decreased IL-2 production by T cells. Our results show that estrogen can modulate the expression of CREMα and lead to IL-2 suppression in human T lymphocytes, thus revealing a molecular link between hormones and the immune system in SLE.