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

Abstract

Strong evidence for the direct modulation of the immune system by opioids is well documented. Mu-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-gamma-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-Ala(2),N:-Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO), a mu-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.

Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression

“…The μ-selective agonist, [ D -Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) has theability to increase the expression of several pro-inflammatory chemokines, including CCL2, CCL5 and CXCL10, in non-activated and PHA-stimulated human PBMCs [72]. This increase in chemokine expression was seen at both the RNA and protein levels and pretreatment with DPhe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), a selective MOR antagonist, abolished the DAMGO-induced increase of CCL2 and CCL5 [72].…”

“…This increase in chemokine expression was seen at both the RNA and protein levels and pretreatment with DPhe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), a selective MOR antagonist, abolished the DAMGO-induced increase of CCL2 and CCL5 [72]. Recent studies have also shown that activation of the MOR by either morphine or DAMGO induces a significant increase in CCL2 expression in primary human neurons [73].…”

Hemodynamic, Thyroid and Immunomodulatory Effects of Heroin in Rats

“…According to our knowledge, this is the first study shows the beneficial effects of diacetylmorphine in immunomodulation through MCP-1 elevation. However, it has been postulated that µ-Opioids are capable of altering inflammatory response and the release of cytokines (Wetzel, et al, 2000). Also (Hatsukari, et al, 2005) reported that morphine-induced modulation of macrophage acts as immunosuppressive due to the requirement of macrophage recruitment.…”

“…Strong evidence has been established in the modulation of the immune system by morphine administration. (Wetzel, et al, 2000) indicated that µ-opioid may change produce MCP-1, which has an important role in proinflammatory reactions and cell-mediated immune responses.…”

Role of Opioidergic System in Humoral Immune Response

“…Exposure to morphine has been shown to suppress production of IFN-, IL-2 and IL-4 by lymphocytes (Lysle et al, 1993;Geber et al, 1975;Bhargava et al, 1994). Wetzel et al, (2000) showed that mu selective agonists increased the expression of the CC chemokine, MCP-1. MCP-1 plays a major role in two distinctly different host responses: cellular immune reactions and responses to active tissue injury (Leonard et al, 1990).…”