TY - JOUR
T1 - Costimulation with interleukin-4 and interleukin-10 induces mast cell apoptosis and cell-cycle arrest
T2 - The role of p53 and the mitochondrion
AU - Bouton, L. Andrew
AU - Ramirez, Carlos D.
AU - Bailey, Daniel P.
AU - Yeatman, C. Fitzhugh
AU - Yue, Joyce
AU - Wright, Harry V.
AU - Domen, Jos
AU - Rosato, Roberto R.
AU - Grant, Steven
AU - Fischer-Stenger, Krista
AU - Ryan, John J.
N1 - Funding Information:
This work was supported in part by generous grants to the Ryan lab from The American Cancer Society (IN-105), the Thomas F. Jeffress and Kate Miller Jeffress Memorial Trust (J-457), the Horsley Cancer Research Fund, the National Institute of Allergy and Infectious Diseases (1R01-AI43433) and the National Cancer Institute (1R01-CA91839), and funding for the Stenger lab from The National Science Foundation (013419).
PY - 2004/12
Y1 - 2004/12
N2 - The aim of this study was to determine the mechanism by which interleukin (IL)-4 + IL-10 costimulation regulates mast cell numbers to maintain immune homeostasis. We employed mouse bone marrow-derived mast cells (BMMC) to measure the effects of IL-4 + IL-10 on survival and cell-cycle progression. p53-Deficient, bax-deficient, and bcl-2 transgenic BMMC were compared to wild-type cells to determine the role of these proteins in apoptosis. The molecular regulation of apoptosis and cell-cycle progression was investigated using flow cytometric analysis, RNase protection, and Western blotting. IL-4 + IL-10 induced BMMC apoptosis and arrest. Apoptosis was p53-dependent. Cell death was accompanied by loss of mitochondrial membrane potential, the importance of which was demonstrated by resistance to IL-4 + IL-10-mediated cell death when Bax was deleted or Bcl-2 was overexpressed. Those cells not killed by apoptosis demonstrated a p53-independent G1 cell-cycle arrest. Apoptosis and arrest may be explained by reduced IL-3 receptor signaling. Costimulation with IL-4 + IL-10 partly controls mast cell homeostasis through a delayed apoptosis and arrest program that is induced by a blockade of IL-3 receptor signaling. The delay in these negative effects would allow the protective effects of mast cell activation to occur for several days.
AB - The aim of this study was to determine the mechanism by which interleukin (IL)-4 + IL-10 costimulation regulates mast cell numbers to maintain immune homeostasis. We employed mouse bone marrow-derived mast cells (BMMC) to measure the effects of IL-4 + IL-10 on survival and cell-cycle progression. p53-Deficient, bax-deficient, and bcl-2 transgenic BMMC were compared to wild-type cells to determine the role of these proteins in apoptosis. The molecular regulation of apoptosis and cell-cycle progression was investigated using flow cytometric analysis, RNase protection, and Western blotting. IL-4 + IL-10 induced BMMC apoptosis and arrest. Apoptosis was p53-dependent. Cell death was accompanied by loss of mitochondrial membrane potential, the importance of which was demonstrated by resistance to IL-4 + IL-10-mediated cell death when Bax was deleted or Bcl-2 was overexpressed. Those cells not killed by apoptosis demonstrated a p53-independent G1 cell-cycle arrest. Apoptosis and arrest may be explained by reduced IL-3 receptor signaling. Costimulation with IL-4 + IL-10 partly controls mast cell homeostasis through a delayed apoptosis and arrest program that is induced by a blockade of IL-3 receptor signaling. The delay in these negative effects would allow the protective effects of mast cell activation to occur for several days.
UR - http://www.scopus.com/inward/record.url?scp=10044279386&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=10044279386&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2004.09.002
DO - 10.1016/j.exphem.2004.09.002
M3 - Article
C2 - 15588938
AN - SCOPUS:10044279386
SN - 0301-472X
VL - 32
SP - 1137
EP - 1145
JO - Experimental Hematology
JF - Experimental Hematology
IS - 12
ER -