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T-Cell Receptor/CD28-Mediated Activation of Human T Lymphocytes Induces Expression of Functional µ-Opioid Receptors

Department of Pharmacology and Toxicology (C.B., J.K., A.B., V.H.) and Department of Immunology (B.S.), University of Magdeburg, Magdeburg, Germany

Opiates function as immunomodulators, partly by their effects on T cells. Opioids act via µ-, -, and -opioid receptors, among which the µ-type is of particular interest, because morphine-like opioids preferentially bind to it. Here we report that µ-opioid receptor mRNA was induced after CD3/28-mediated activation of primary human T lymphocytes and Jurkat T cells, neither of which expresses the gene constitutively. Moreover, a reporter gene construct containing 2624 base pairs of the µ-opioid receptor promoter was transactivated by CD3/28 stimulation. Transcriptional induction of the µ-opioid receptor gene was mediated by activator protein-1 (AP-1), nuclear factor-B, and nuclear factor of activated T cells (NFAT). NFAT was found to bind to three sequences of the µ-opioid receptor promoter, located at nucleotides -1064, -785, and -486. Although the -486 element is in close proximity to a putative AP-1 site, there was no evidence for a combined AP-1/NFAT site. Furthermore, we demonstrated that the induction of inter-leukin-2 mRNA and protein in activated T cells was inhibited by morphine in cells, in which µ-opioid receptors had been induced by CD3/28 monoclonal antibodies (mAbs), and that this effect was blocked by the µ-opioid receptor-specific antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂. CD3/28 mAb-induced interleukin-2 transcription was also inhibited by the opioids fentanyl and loperamide. This indicates that the induced µ-opioid receptor mRNA is translated into functional receptor protein. Furthermore, a µ-opioid receptor-enhanced green fluorescent protein-fusion protein was localized in membranes of Jurkat cells and internalized in response to [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin but not morphine. In conclusion, these data emphasize the role of opioids in the modulation of T lymphocyte signaling.

Address correspondence to: Dr. Jürgen Kraus, Dept. of Pharmacology and Toxicology, Magdeburg University, 44 Leipzigerstrasse, 39120 Magdeburg, Germany. E-mail: juergen.kraus{at}med.ovgu.de