Morphine exacerbates HIV1 Tat-induced cytokine production in astrocytes through convergent effets on ([Ca 2+ ]i, NF-κB trafficking and transcription. PLoS One 2008

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-kB) 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-kB inhibitor parthenolide provided evidence that Tat6morphine-induced release of MCP-1, IL-6 and TNF-a by astrocytes is NF-kB dependent. The nuclear export inhibitor, leptomycin B, blocked the nucleocytoplasmic shuttling of NF-kB; causing p65 (RelA) accumulation in the nucleus, and significantly attenuated cytokine production in Tat6morphine exposed astrocytes. Similarly, chelating intracellular calcium ([Ca2+]i) blocked Tat6morphine-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 Tat6morphine is sufficient to activate NF-kB and cytokine production, 2) the release of MCP-1 and IL-6 by Tat6morphin