ACTIVATION-INDUCED APOPTOSIS IN HUMAN MACROPHAGES - DEVELOPMENTAL REGULATION OF A NOVEL CELL-DEATH PATHWAY BY MACROPHAGE-COLONY-STIMULATINGFACTOR ACID INTERFERON-GAMMA

Activated macrophages (M phi s) are important participants in host def ense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the i mmune system is programmed cell death, or apoptosis. Monocytes are kno wn to undergo spontaneous apoptosis upon leaving the circulation unles s provided with specific survival signals, but mature tissue M phi s a re more robust cells, and it was not clear that they could be similarl y regulated by apoptosis. We now show that during differentiation mono cytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initia tes apoptosis after activation with specific stimuli (zymosan and phor bol esters). Sensitivity to activation-induced apoptosis was developme ntally determined, being downregulated by the maturation-promoting cyt okine macrophage colony-stimulating factor but stably upregulated by e ven transient exposure to the proinflammatory cytokine interferon gamm a (IFN-gamma). Apoptosis began within 2-4 h of activation, occurred in >95% of susceptible cells, and in mixed cocultures selectively affect ed only those M phi s with a history of IFN-gamma priming. Consistent with a possible role for protein kinase C in the signaling pathway lea ding to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosan-induced apoptosis. Our studies describe a novel form of activation-induced M phi apoptosis which is developmentally regulated by two physiologically relevant cytokines. W e speculate that apoptosis may serve to restrict the destructive poten tial of inflammatory M phi s.