Fas ligand, Bcl-2, granulocyte colony-stimulating factor, and p38 mitogen-activated protein kinase: Regulators of distinct cell death and survival pathways in granulocytes
- Author(s)
- Villunger, A; O'Reilly, LA; Holler, N; Adams, J; Strasser, A;
- Details
- Publication Year 2000-09-04,Volume 192,Issue #5,Page 647-657
- Journal Title
- JOURNAL OF EXPERIMENTAL MEDICINE
- Publication Type
- Journal Article
- Abstract
- 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 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 actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Eel-a-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.
- Publisher
- ROCKEFELLER UNIV PRESS
- Keywords
- DRUG-INDUCED APOPTOSIS; HUMAN NEUTROPHILS; LEUKEMIA-CELLS; DIFFERENTIAL EXPRESSION; PROAPOPTOTIC ACTIVITY; DOWN-REGULATION; DEFICIENT MICE; MAP KINASES; MACROPHAGES; A1
- Publisher's Version
- https://doi.org/10.1084/jem.192.5.647
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- Refer to copyright notice on published article.
Creation Date: 2000-09-04 12:00:00