Exposure of cultured murine peritoneal macrophages to low concentrations of beryllium induces increases in intracellular calcium concentrations and stimulates DNA synthesis.
Exposure of humans to beryllium dusts can induce a specific form of chronic pneumonitis that consists mainly of noncaseating granulomas in the lungs. Multiple studies have documented both genetic and immune components of chronic berylliosis. Much work has focused on T cells and their reactivity in berylliosis, but less work has focused on the end effector cells in granulomatous inflammation, macrophages. Because macrophages must become activated to form granulomas, and they become activated by responding to numerous immunomodulatory signals, we investigated the effects of beryllium (BeCl2) on a central signal transduction pathway in macrophages, increases in intracellular calcium ([Ca2+]i). Exposure of cultured murine peritoneal macrophages to low, nontoxic concentrations induced successive spikes or oscillations in [Ca2+]i. Concentrations as low as 5 nM induced significant increases in [Ca2+]i. The source of the increased [Ca2+]i was exclusively extracellular in that increases in [Ca2+]i could be completely blocked by chelating extracellular Ca2+, were inhibited by the Ca2+ channel blocker verapamil, and exposure of macrophages to BeCl2 had no effect on IP3 concentrations. DNA synthesis, a Ca2+-sensitive function, was enhanced in dividing 1LN cells and induced de novo in quiescent macrophages. Furthermore, BeCl2 enhanced DNA synthesis in the absence of coexposure to the protein kinase C activator phorbol myristate acetate. These data support the hypothesis that beryllium toxicity is in part the result of altered Ca2+ metabolism in mononuclear phagocytes consequent to reversible opening of plasma membrane channels.
Misra
U K
UK
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gawdi
G
G
Pizzo
S V
SV
Lewis
J G
JG
D000818:Animals; D001608:Beryllium / Q000494:pharmacology* / Q000633:toxicity; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D007424:Intracellular Fluid / Q000737:chemistry; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009532:Nickel / Q000494:pharmacology; D009994:Osmolar Concentration; D015032:Zinc / Q000494:pharmacology
D002104:Cadmium; D003035:Cobalt; D009532:Nickel; D004247:DNA; D015032:Zinc; D001608:Beryllium; D002118:Calcium