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Published online before print February 5, 2008

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(Journal of Leukocyte Biology. 2008;83:956-963.)
© 2008 by Society for Leukocyte Biology

DAMGO-induced expression of chemokines and chemokine receptors: the role of TGF-β1

Christine Happel^*,, Amber D. Steele^,,1, Matthew J. Finley^*,, Michele A. Kutzler^*,,,2 and Thomas J. Rogers^*,,,,3

^* Fels Institute for Cancer Research and Molecular Biology,
Center for Substance Abuse Research, Departments of
Microbiology and Immunology and
Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

³ Correspondence: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA. E-mail: rogerst{at}temple.edu

Studies from a number of laboratories suggest that modulation of cytokine expression plays an integral role in the immunomodulatory activity of opioids. Previously, our laboratory reported that activation of the µ-opioid receptor induced the expression of CCL2, CCL5, and CXCL10, as well as CCR5 and CXCR4. Previous work has also suggested the possibility that TGF-β may participate in the opioid-induced regulation of immune competence, and in the present study, we set out to determine the role of this cytokine in the control of chemokine and chemokine receptor expression. We found that D-ala²,N-Me-Phe⁴-Gly-ol⁵enkephalin (DAMGO), a highly selective µ-opioid agonist, induced the expression of TGF-β1 expression at the protein and mRNA levels. In turn, the addition of TGF-β1 was found to induce CCL5 and CXCR4 expression but not CCL2, CXCL10, or CCR5. Further analysis showed that pretreatment with neutralizing anti-TGF-β1 blocked the ability of DAMGO to induce CCL5 or CXCR4. Similarly, pretreatment with cycloheximide prevented CCL5 or CXCR4 mRNA expression, consistent with the observation that DAMGO induction of chemokine and chemokine receptor expression requires newly synthesized TGF-β1 protein. These results describe a common molecular basis for the activation of chemokine and chemokine receptor expression and may permit the development of strategies to inhibit certain undesirable immunological properties of µ-opioid agonists such as morphine and heroin.

Key Words: opioid • CCL5 • CXCR4