Chronic morphine inhibits interleukin-2 (IL-2) at both the transcriptional and protein synthesis levels. The molecular mechanisms by which morphine decreases IL-2 are not fully understood. The production of IL-2 is tightly regulated by several transcription factors that bind to the IL-2 promoter. Herein, we show that chronic morphine treatment results in an increase in cAMP levels with a concurrent up-regulation of the cAMP inducible repressor inducible cAMP early repressor (ICER)/cAMP response element modulator (CREM) and down-regulation of p-cAMP-response element-binding protein (CREB) in activated T cells. Furthermore, ICER competes for p-CREB binding to the cAMP-responsive elements (CREs) site. This leads to the uncoupling of CBP/p300 thereby abrogating IL-2 transcription. Overexpression of either antisense CREM or CREB plasmid rescued morphine-induced inhibition of IL-2 promoter activity and protein production. In addition, we also found that chronic morphine treatment inhibited the acetylation and trimethylation of histones and decreased both DNA demethylation and accessibility of the IL-2 promoter. These findings suggest that chronic morphine treatment may function through both transcriptional and epigenetic mechanisms to inhibit IL-2 production.
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