Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-α production in human macrophages

Michael Mayne, Clark P. Holden, Avindra Nath, Jonathan D. Geiger

Research output: Contribution to journalArticle

Abstract

HIV-1 protein Tat is neurotoxic and increases macrophage and microglia production of TNF-α, a cytopathic cytokine linked to the neuropathogenesis of HIV dementia. Others have shown that intracellular calcium regulates TNF- α 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-α 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-α 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-α production.

Original languageEnglish (US)
Pages (from-to)6538-6542
Number of pages5
JournalJournal of Immunology
Volume164
Issue number12
DOIs
StatePublished - Jun 15 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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