Stimulation of chemokine expression following mu-opioid administration, HIV-1 infection, and activation of certain seven transmembrane G protein-coupled receptors (Immune deficiency)

The following studies investigated the effect of a μ-opioid agonist on chemokine expression. DAMGO pretreatment of PBMCs resulted in a significant increase in RANTES and IP-10 expression, while only high doses of DAMGO enhanced MCP-1 levels. Selective μ-antagonist pretreatment blocked the induction of MCP-1 and RANTES transcripts, suggesting chemokine induction was mediated through the μ-opioid receptor. Pretreatment with an NFκB inhibitor resulted in inhibition of the DAMGO-induced elevation in MCP-1 and RANTES expression, while IP-10 levels remained at control levels. Moreover, anti-TGF-β administration blocked the DAMGO-induced enhancement of RANTES expression. Dichotomous effects on chemokine production were observed after DAMGO treatment of X4 and R5 HIV-1-infected PBMCs. These findings provide evidence that opioids modulate immune function by altering chemokine expression, which may be mediated, in part, by NFκB activation or cytokine expression.; Examination of chemokine expression during the first 72 hours of X4 HIV-1 infection revealed augmented levels of MCP-1, RANTES, and IP-10, while R5 HIV-1 infection enhanced MCP-1 and IP-10 production, but not RANTES protein. Binding of UV-inactivated X4 and R5 HIV-1 induced MCP-1 expression, but failed to alter the production of IP-10, suggesting that the induction of IP-10 is dependent on downstream events following viral internalization. HIV-1 gp120 treatment stimulated MCP-1 expression, although IP-10 protein levels remained at control levels, while anti-gp120 pretreatment inhibited the HIV-1-induced elevation of both MCP-1 and IP-10. HIV-1 Tat administration to PBMCs resulted in a significant increase in the production of IP-10. These data provide additional evidence that chemokine regulation by HIV-1 infection is mediated by distinct mechanisms.; Activation of μ-opioid or formyl peptide receptors resulted in heterologous desensitization of CCR5, leading to decreased susceptibility to R5 HIV-1 infection. These results suggest that FPR, FPRL1, and μ-opioid receptors may play important roles not only in host defense and immunological responses, but also in the fine-tuning of cell activation in the presence of multiple stimuli. Taken together, our data suggest that activation of G protein-coupled receptors results in the modulation of chemokine expression by cells of the immune system, as well as, heterologous desensitization, leading to altered susceptibility to HIV-1 infection.