IFN-gamma induces apoptosis in developing mast cells.
Mast cells are critical effectors of allergic disease, and are now implicated in immune responses observed in arthritis, multiple sclerosis, and heart disease. Because of their role in inflammation, understanding how mast cells develop is of clinical importance. In this study we determined the effects of IFN-gamma on mast cell survival. Using in vitro culture of bone marrow cells in IL-3 plus stem cell factor, we found that the addition of IFN-gamma induced apoptosis, as exhibited by the presence of subdiploid DNA and caspase activation. IFN-gamma-mediated apoptosis was Stat1-dependent, and was accompanied by loss of mitochondrial membrane potential. Apoptosis was reduced in cultures of bone marrow cells derived from p53- or Bax-deficient mice, as well as H2K-Bcl-2 transgenic mice. IFN-gamma hyperresponsiveness has been shown to result in inflammatory disease and death in mice lacking the regulatory protein suppressor of cytokine signaling (SOCS)-1. Bone marrow cells from SOCS-1 knockout (KO) mice failed to give rise to viable mast cells after culture in IL-3 plus stem cell factor, with profound apoptosis occurring as the cultures matured. However, bone marrow cells lacking both SOCS-1 and IFN-gamma survived normally. This in vitro defect in mast cell development was recapitulated in vivo. SOCS-1 KO mice demonstrated a 67% decrease in peritoneal mast cell numbers relative to wild-type mice, a deficiency that was reversed in SOCS-1/IFN-gamma KO mice. These data demonstrate the potent regulatory effects of IFN-gamma on mast cell survival and show that this cytokine can elicit mast cell death in vitro and in vivo.
Mann-Chandler
Meredith N
MN
Department of Biology, Virginia Commonwealth University, Richmond, VA 23284-2012, USA.
Kashyap
Mohit
M
Wright
Harry V
HV
Norozian
Farnaz
F
Barnstein
Brian O
BO
Gingras
Sébastien
S
Parganas
Evan
E
Ryan
John J
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000502:physiology; D002452:Cell Count; D004268:DNA-Binding Proteins / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology*; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D012097:Repressor Proteins / Q000502:physiology; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D019009:Proto-Oncogene Proteins c-kit