Abstract
The mechanism of macrophage activation by Ca 2+ ionophore was studied. Peritoneal exudate macrophages from normal guinea pigs exposed continuously to or pulse treated for 1 hr with the ionophore, A23187, were activated, manifesting increased glucose consumption and inhibition of migration. Highly purified macrophages were also activated as effectively as crude macrophage preparations, and the culture supernatant of spleen lymphocytes treated with A23187 lacked a macrophage activating effect, showing that the macrophage activation resulted from the direct effect of A23187 on macrophages, not via lymphokines produced by lymphocytes. The macrophage activation by A23187 was suppressed in the presence of EGTA, but the suppressive effect was overcome by the addition of Ca 2+, but not of Mg 2+. A dilution experiment with Ca 2+ and Mg 2+ during the pulse treatment of cells with A23187 revealed that the activating effect of A23187 was more dependent on Ca 2+ content than Mg 2+. In addition, the Ca 2+ antagonist, nicardipine, was found to suppress the activating effect of A23187. The Ca 2+ uptake into macrophages was increased by treatment with A23187. These results indicate that Ca 2+ influx into cells is primarily important in the macrophage activating effect of A23187. Trifluoperazine (TFP: a specific inhibitor of calmodulin that is an intracellular Ca 2+ receptor protein) was found to inhibit the activating effect of A23187. Further, the cyclic nucleotides, dibutyryl-cAMP and −cGMP, did not activate macrophages. Therefore, macrophage activation was presumed not to be directly mediated by cyclic nucleotides. All these findings show that macrophage activation with the ionophore proceeds by the following scheme: Ca 2+ influx → activation of Ca 2+ receptor protein, calmodulin → activation of calmodulin-regulated enzymes → metabolic changes, activation. TFP was found to suppress the macrophage activation with highly purified guinea pig macrophage activation factor/macrophage migration inhibitory factor (MIF/MAF) or lipopoly-saccharide (LPS), suggesting that calmodulin also played an important role in macrophage activation with MIF/MAF or LPS.
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