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Original Article

Andreas Villunger^a, Lorraine A. O'Reilly^a, Nils Holler^b, Jerry Adams^a, and Andreas Strasser^a

^a The Walter and Eliza Hall Institute, Melbourne, Victoria 3050, Australia
^b Institute of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland
The Walter and Eliza Hall Institute, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.61-3-9347-085261-3-9345-2624

strasser{at}wehi.edu.au

The short life span of granulocytes, which limits many inflammatory responses, is thought to be influenced by the Bcl-2 protein family, death receptors such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), and proinflammatory cytokines like granulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spontaneous 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 unaffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in lpr 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 actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Bcl-2–controlled pathway, whereas CD95 regulates a distinct pathway to apoptosis that is not required for either their spontaneous or drug-induced death. Moreover, p38 MAPK signaling contributes to granulocyte survival rather than their apoptosis.

Key Words: apoptosis • Bcl-2 • Fas ligand • p38 mitogen-activated protein kinase • granulocyte colony-stimulating factor

© 2000 The Rockefeller University Press

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