Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages.
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.
Mayne
M
M
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
Holden
C P
CP
Nath
A
A
Geiger
J D
JD
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000276:immunology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004963:Estrenes / Q000494:pharmacology; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007424:Intracellular Fluid / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D037342:Pertussis Toxin; D011760:Pyrrolidinones / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010738:Type C Phospholipases / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
D015220:Calcium Channels; D004963:Estrenes; D015696:Gene Products, tat; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011760:Pyrrolidinones; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D054322:tat Gene Products, Human Immunodeficiency Virus; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D015544:Inositol 1,4,5-Trisphosphate; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D002118:Calcium