Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex multifactorial pathogenesis. T lymphocytes play a critical role in disease pathogenesis and display abnormal gene expression and poor interleukin (IL)-2 production. We previously showed that the expression of the transcriptional repressor cyclic AMP response element modulator alpha (CREM alpha) is increased in SLE T cells and contributes to reduced IL-2 production. Although 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 CREM alpha in human T lymphocytes.We show that exposure of human T cells to 17-beta-estradiol leads to a dose-dependent increase in CREM alpha mRNA expression, and this increase appears to be mediated through the estrogen receptors alpha and beta. We show that the increased expression of CREM alpha 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 a dose-dependent decrease in IL-2 mRNA and cytokine production by T cells. Finally, the effect of beta-estradiol on CREM alpha is observed more frequently in T cells from women than from men. We conclude that estrogen can modulate the expression of CREM alpha and lead to IL-2 suppression in human T lymphocytes, thus revealing a molecular link between hormones and the immune system in SLE. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00506