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Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca(2+)](i), NF-kappaB trafficking and transcription
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
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2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 12, e4093- p.Article in journal (Refereed) Published
Abstract [en]

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-kappaB) 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-kappaB inhibitor parthenolide provided evidence that Tat+/-morphine-induced release of MCP-1, IL-6 and TNF-alpha by astrocytes is NF-kappaB dependent. The nuclear export inhibitor, leptomycin B, blocked the nucleocytoplasmic shuttling of NF-kappaB; causing p65 (RelA) accumulation in the nucleus, and significantly attenuated cytokine production in Tat+/-morphine exposed astrocytes. Similarly, chelating intracellular calcium ([Ca(2+)](i)) blocked Tat+/-morphine-evoked MCP-1 and IL-6 release, while artificially increasing the concentration of extracellular Ca(2+) reversed this effect. Taken together, these results demonstrate that: 1) exposure to Tat+/-morphine is sufficient to activate NF-kappaB and cytokine production, 2) the release of MCP-1 and IL-6 by Tat+/-morphine are highly Ca(2+)-dependent, while TNF-alpha appears to be less affected by the changes in [Ca(2+)](i), and 3) in the presence of Tat, exposure to opiates augments Tat-induced NF-kappaB activation and cytokine release through a Ca(2+)-dependent pathway.

Place, publisher, year, edition, pages
2008. Vol. 3, no 12, e4093- p.
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Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-103067DOI: 10.1371/journal.pone.0004093ISI: 000265466600014PubMedID: 19116667OAI: oai:DiVA.org:uu-103067DiVA: diva2:217385
Available from: 2009-05-14 Created: 2009-05-14 Last updated: 2011-11-23Bibliographically approved

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Yakovleva, TatianaBazov, IgorBakalkin, Georgy
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