Mechanism of calcium ionophore A23187-induced priming of bone marrow-derived macrophages for tumor cell killing: relationship to priming by interferon.

Interferon primes macrophages for tumor cell killing by rendering them sensitive to triggering agents such as lipopolysaccharide. In an attempt to determine the nature of the priming signal, we tested phorbol 12-myristate 13-acetate, diacylglycerol, platelet-activating factor, arachidonic acid, leukotriene B4, and the calcium ionophore A23187 for their ability to prime mouse bone marrow-derived macrophages for activation to kill P815 mastocytoma target cells. The ionophore A23187 was the only substance that was able to replace the interferon priming signal. A23187 priming appeared to be due in part to induction of interferon alpha/beta in the macrophage cultures, since its effect was partially but specifically blocked by antibody to interferon alpha/beta. Consistent with this was the observation that A23187 induced interferon alpha/beta production in macrophage cultures. The fact that A23187 priming was not completely reversed by antibody to interferon would suggest that factors unrelated to interferon induction also played a role in macrophage priming. The failure of phorbol myristate acetate or diacylglycerol to prime macrophages for tumor cell killing would suggest that activation of protein kinase C is not sufficient for priming. Thus, A23187 appears to provide the priming signal for macrophage killing through the combination of interferon- and non-interferon-induced mechanisms.