TGFbeta1 induces mast cell apoptosis.
Mast cells are potent effectors of the inflammatory response, playing an important role in atopy, bacterial immunity, and animal models of arthritis, multiple sclerosis, and heart disease. Hence controlling mast cell numbers and responsiveness is essential for preventing inflammatory disease. We demonstrate that the cytokine transforming growth factor (TGF) beta1 is a potent inducer of mast cell apoptosis, a finding that was consistent in cultured mouse bone marrow-derived mast cells, peritoneal mast cells, and human mast cells. Cell death appeared to be caused by TGF-mediated repression of interleukin-3 (IL-3) receptor expression and function, leading to mitochondrial damage and activation of an apoptotic cascade acting via p53 and caspases. Although IL-3 receptor expression was reduced within 1 day of TGFbeta1 stimulation, apoptosis required at least 3 days to occur. This delay in onset is postulated to allow protective mast cell effector functions, protecting the host from infection while preventing the establishment of chronic inflammation. Our data support the theory that TGFbeta1 is an inhibitor of mast cell survival. The widespread expression of TGFbeta1 offers this cytokine as an ideal candidate for control of mast cell homeostasis.
Norozian
Farnaz
F
Department of Biology, Virginia Commonwealth University, Richmond, VA 23284-2012, USA.
Kashyap
Mohit
M
Ramirez
Carlos D
CD
Patel
Neha
N
Kepley
Christopher L
CL
Barnstein
Brian O
BO
Ryan
John J
JJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000037:antagonists & inhibitors / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016185:Receptors, Interleukin-3; D050799:STAT5 Transcription Factor; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D019009:Proto-Oncogene Proteins c-kit