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µ-Opioid Induction of Monocyte Chemoattractant Protein-1, RANTES, and IFN--Inducible Protein-10 Expression in Human Peripheral Blood Mononuclear Cells¹

Michele A. Wetzel^*,,, Amber D. Steele^*,,, Toby K. Eisenstein^*,, Martin W. Adler^,, Earl E. Henderson^*,, and Thomas J. Rogers^2,*,,

Departments of ^* Microbiology and Immunology and Pharmacology, Center for Substance Abuse Research and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140

Strong evidence for the direct modulation of the immune system by opioids is well documented. µ-Opioids have been shown to alter the release of cytokines important for both host defense and the inflammatory response. Proinflammatory chemokines monocyte chemoattractant protein-1 (MCP-1), RANTES, and IFN--inducible protein-10 (IP-10) play crucial roles in cell-mediated immune responses, proinflammatory reactions, and viral infections. In this report, we show that [D-Ala²,N-Me-Phe⁴,Gly-ol⁵]enkephalin (DAMGO), a µ-opioid-selective agonist, augments the expression in human PBMCs of MCP-1, RANTES, and IP-10 at both the mRNA and protein levels. Because of the proposed relationship between opioid abuse and HIV-1 infection, we also examined the impact of DAMGO on chemokine expression in HIV-infected cells. Our results show that DAMGO administration induces a significant increase in RANTES and IP-10 expression, while MCP-1 protein levels remain unaffected in PBMCs infected with the HIV-1 strain. In contrast, we show a dichotomous effect of DAMGO treatment on IP-10 protein levels expressed by T- and M-tropic HIV-infected PBMCs. The differential modulation of chemokine expression in T- and M-tropic HIV-1-infected PBMCs by opioids supports a detrimental role for opioids during HIV-1 infection. Modulation of chemokine expression may enhance trafficking of potential noninfected target cells to the site of active infection, thus directly contributing to HIV-1 replication and disease progression to AIDS.

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