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

Abstract

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

• Authors: M Mayne, C P Holden, A Nath, J D Geiger
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 164 Issue 12 Pg. 6538-42 (Jun 15 2000) ISSN: 0022-1767 [Print] United States
• PMID: 10843712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium Channels
• Estrenes
• Gene Products, tat
• ITPR1 protein, human
• Inositol 1,4,5-Trisphosphate Receptors
• Pyrrolidinones
• Receptors, Cytoplasmic and Nuclear
• Tumor Necrosis Factor-alpha
• Virulence Factors, Bordetella
• tat Gene Products, Human Immunodeficiency Virus
• 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
• Inositol 1,4,5-Trisphosphate
• Pertussis Toxin
• Type C Phospholipases
• Calcium

Topics

• Calcium (metabolism)
• Calcium Channels (physiology)
• Calcium Signaling (immunology)
• Cells, Cultured
• Dose-Response Relationship, Immunologic
• Estrenes (pharmacology)
• Gene Products, tat (physiology)
• HIV-1 (physiology)
• Humans
• Inositol 1,4,5-Trisphosphate (metabolism)
• Inositol 1,4,5-Trisphosphate Receptors
• Intracellular Fluid (metabolism)
• Macrophages (drug effects, immunology, metabolism)
• Pertussis Toxin
• Pyrrolidinones (pharmacology)
• Receptors, Cytoplasmic and Nuclear (physiology)
• Time Factors
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis)
• Type C Phospholipases (physiology)
• Virulence Factors, Bordetella (pharmacology)
• tat Gene Products, Human Immunodeficiency Virus