QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.046029v1 74/2/496    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Börner, C. Articles by Höllt, V. PubMed PubMed Citation Articles by Börner, C. Articles by Höllt, V.

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