SHIP represses Th2 skewing by inhibiting IL-4 production from basophils.
We report that SHIP(-/-) mice, compared to SHIP(+/+) mice, are Th2 skewed with elevated serum IgE and twice as many splenic CD4(+) Th2 cells that, when stimulated with anti-CD3, produce more IL-4 and less IFN-γ. Exploring the reason for this Th2 skewing, we found that freshly isolated SHIP(-/-) splenic and bone marrow basophils are present in elevated numbers and secrete far more IL-4 in response to IL-3 or to FcεRI stimulation than do WT basophils. These SHIP(-/-) basophils markedly skew wild-type macrophage colony stimulating factor-derived macrophages toward an M2 phenotype, stimulate OT-II CD4(+) Th cells to differentiate into Th2 cells, and trigger SHIP(+/+) B cells to become IgE-producing cells. All these effects are completely abrogated with neutralizing anti-IL-4 Ab. Exploring the cell signaling pathways responsible for hyperproduction of IL-4 by SHIP(-/-) basophils, we found that IL-3-induced activation of the PI3K pathway is significantly enhanced and that PI3K inhibitors, especially a p110α inhibitor, dramatically suppresses IL-4 production from these cells. In vivo studies, in which basophils were depleted from mast cell-deficient SHIP(+/+) and SHIP(-/-) mice, confirmed the central role that basophils play in the Th2 skewing of naive SHIP-deficient mice. Taken together, these studies demonstrate that SHIP is a potent negative regulator of IL-4 production from basophils and thus may be a novel therapeutic target for Th1- and Th2-related diseases.
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
Etsushi
E
Kuroda
Frann
F
Antignano
Victor W
VW
Ho
Michael R
MR
Hughes
Jens
J
Ruschmann
Vivian
V
Lam
Toshiaki
T
Kawakami
William G
WG
Kerr
Kelly M
KM
McNagny
Laura M
LM
Sly
Gerald
G
Krystal
D000818:Animals; D001491:Basophils / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood; D000072181:Inositol Polyphosphate 5-Phosphatases; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D012097:Repressor Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases