Fas ligand, Bcl-2, granulocyte colony-stimulating factor, and p38 mitogen-activated protein kinase: Regulators of distinct cell death and survival pathways in granulocytes

The short life span of granulocytes, which Limits many inflammatory respons es, is thought to be influenced by the Bcl-2 protein family, death receptor s such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mi togen-activated protein kinase (MAPK), and proinflammatory cytokines like g ranulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spont aneous apoptosis of granulocytes in culture and that induced by Fas ligand or chemotherapeutic drugs, using cells from normal, CD95-deficient lpr, or vav-bcl-2 transgenic mice. CD95-induced apoptosis, which required receptor aggregation by recombinant Fas ligand or the membrane-bound ligand, was una ffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in Ipv granulocytes but were suppressed by G-CSF treatment or Bcl-2 overexpression. Although activation of p38 MAPK has been implicated in granulocyte death, their apoptosis actua lly was markedly accelerated by specific inhibitors of this kinase. These r esults suggest that G-CSF promotes granulocyte survival largely through the Eel-a-controlled pathway, whereas CD95 regulates a distinct pathway to apo ptosis that is not required for either their spontaneous or drug-induced de ath. Moreover, p38 MAPK signaling contributes to granulocyte survival rathe r than their apoptosis.