Transcriptional and Epigenetic Regulation of Interleukin-2 Gene in Activated T Cells by Morphine*
- ‡Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455 and the §Department of Surgery, Veterans Affairs Medical Center, Minneapolis, Minnesota 55417
- 1 To whom correspondence should be addressed: Dept. of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455. Tel.: 612-624-5983; Fax: 612-625-8408; E-mail: royxx002{at}umn.edu.
Abstract
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.
Footnotes
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↵2 The abbreviations used are: IL-2, interleukin-2; CRE, cAMP-responsive element; CREB, cAMP-response element-binding protein; CREM, cAMP response element modulator; ICER, inducible cAMP early repressor; CBP, CREB binding protein; MORKO, μ-opioid receptor knockout; WT, wild type; ChIP, chromatin immunoprecipitation analysis; Ab, antibody; CD28RE, CD28-responsive element; RT, reverse transcriptase.
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↵* This work was supported by National Institutes of Health Grants RO1DA12104, KO2DA015349, and P50DA11806 (to S. R.) and, T32DA07097 (to J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received May 8, 2006.
- Revision received January 12, 2007.
- The American Society for Biochemistry and Molecular Biology, Inc.
