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Release of Calcium from Inositol 1,4,5-Trisphosphate Receptor-Regulated Stores by HIV-1 Tat Regulates TNF- Production in Human Macrophages¹

Michael Mayne^*, Clark P. Holden^*, Avindra Nath and Jonathan D. Geiger^2,*

^* Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada; and Departments of Neurology, Microbiology, and Immunology, University of Kentucky, Lexington, KY 40506

HIV-1 protein Tat is neurotoxic and increases macrophage and microglia production of TNF-, a cytopathic cytokine linked to the neuropathogenesis of HIV dementia. Others have shown that intracellular calcium regulates TNF- production in macrophages, and we have shown that Tat releases calcium from inositol 1,4,5-trisphosphate (IP₃) receptor-regulated stores in neurons and astrocytes. Accordingly, we tested the hypothesis that Tat-induced TNF- production was dependent on the release of intracellular calcium from IP₃-regulated calcium stores in primary macrophages. We found that Tat transiently and dose-dependently increased levels of intracellular calcium and that this increase was blocked by xestospongin C, pertussis toxin, and by phospholipase C and type 1 protein kinase C inhibitors but not by protein kinase A or phospholipase A₂ inhibitors. Xestospongin C, BAPTA-AM, U73122, and bisindolylmalemide significantly inhibited Tat-induced TNF- production. These results demonstrate that in macrophages, Tat-induced release of calcium from IP₃-sensitive intracellular stores and activation of nonconventional PKC isoforms play an important role in Tat-induced TNF- production.

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