Abstract

Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-κB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-κB inhibitor parthenolide provided evidence that Tat±morphine-induced release of MCP-1, IL-6 and TNF-α by astrocytes is NF-κB dependent. The nuclear export inhibitor, leptomycin B, blocked the nucleocytoplasmic shuttling of NF-κB; causing p65 (RelA) accumulation in the nucleus, and significantly attenuated cytokine production in Tat±morphine exposed astrocytes. Similarly, chelating intracellular calcium ([Ca2+]i) blocked Tat±morphine-evoked MCP-1 and IL-6 release, while artificially increasing the concentration of extracellular Ca2+ reversed this effect. Taken together, these results demonstrate that: 1) exposure to Tat±morphine is sufficient to activate NF-κB and cytokine production, 2) the release of MCP-1 and IL-6 by Tat±morphine are highly Ca2+-dependent, while TNF-α appears to be less affected by the changes in [Ca2+]i, and 3) in the presence of Tat, exposure to opiates augments Tat-induced NF-κB activation and cytokine release through a Ca2+-dependent pathway.

Highlights

  • Among human immunodeficiency virus type 1 (HIV-1)-infected individuals, injection drug users are at greater risk than nonusers of developing HIV-associated neurological impairment, as well as other opportunistic infections [1,2,3]

  • C-Rel is a member of the NF-kB/Rel family of transcription factors that are known to be involved in regulating expression of MCP-1 and other chemokine genes in a variety of both human and mouse tissues [38,39] including astrocytes [40]

  • Based on long-standing evidence of the involvement of NF-kB in the production of inflammatory mediators, we predicted that opiates would potentiate the effects of HIV-1 Tat on proinflammatory cytokine production by astrocytes through signals converging at NF

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Summary

Introduction

Among human immunodeficiency virus type 1 (HIV-1)-infected individuals, injection drug users are at greater risk than nonusers of developing HIV-associated neurological impairment, as well as other opportunistic infections [1,2,3]. Does injection drug use provide a mode for viral spread, but the opioid system (i.e., endogenous opioid peptides and receptors) plays a fundamental role in modifying, and in many cases exacerbating the pathogenesis of neuro-acquired immune deficiency syndrome (neuroAIDS) [4,5,6]. Brain regions expressing a high number/density of m-opioid receptors (MOP), such as the striatum and the hippocampus, have increased viral loads and are preferentially decimated by HIV infection (reviewed in [4,5,6]). M-Opioid receptor-expressing astrocytes in particular may be an important site of convergence for opiate drug-HIV-1 actions. The mechanisms underlying opiate-induced increases of chemokine expression and release in astrocytes exposed to HIV-1 protein are incompletely understood

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