Role of calcium in the activation of mouse peritoneal macrophages: induction of NO synthase by calcium ionophores and thapsigargin.
Bacterial lipopolysaccharide (LPS) has been recognized as one of the most potent activating signals for mouse peritoneal macrophages. In macrophages primed by interferon-gamma (IFN-gamma) or trehalose dimycolate (TDM), LPS induces NO synthase and the events associated with a high nitric oxide output: antitumor and antiparasitic activities. In the present report, it is shown that drugs (calcium ionophores or thapsigargin) which elevate the concentration of cytosolic calcium, [Ca2+]i, induce NO synthase and antitumor activities in primed macrophages, mimicking LPS action. Calcium ionophores and thapsigargin trigger NO synthase activity in macrophages primed in vivo by TDM, in thioglycollate-elicited macrophages primed in vitro by IFN-gamma, and in IFN-gamma-treated EMT6 adenocarcinoma cells. However, activation of TDM-primed macrophages by LPS does not seem to involve calcium fluxes: (i) no change in [Ca2+]i was detectable in TDM-primed macrophages loaded with Fura-2 and exposed to LPS, and (ii) activation of TDM-primed macrophages by LPS can be obtained in the presence of 4 mM EGTA. NO synthase expression is thus controlled in primed macrophages by two different pathways; calcium ionophores can replace LPS but do not act through the same intracellular cascade.
Raddassi
K
K
URA CNRS 1116, Bâtiment 432, Université Paris Sud, Orsay, France.
Berthon
B
B
Petit
J F
JF
Lemaire
G
G
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D003311:Cord Factors / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019001:Nitric Oxide Synthase; D011994:Recombinant Proteins; D015398:Signal Transduction; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014407:Tumor Cells, Cultured / Q000276:immunology
D003311:Cord Factors; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D013729:Terpenes; D000001:Calcimycin; D015759:Ionomycin; D019284:Thapsigargin; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D000252:Calcium-Transporting ATPases; D002118:Calcium