SHIP represses Th2 skewing by inhibiting IL-4 production from basophils

J Immunol. 2011 Jan 1;186(1):323-32. doi: 10.4049/jimmunol.1002778. Epub 2010 Dec 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basophils / immunology*
  • Basophils / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Line
  • Cells, Cultured
  • Immunoglobulin E / biosynthesis
  • Immunoglobulin E / blood
  • Inositol Polyphosphate 5-Phosphatases
  • Interleukin-4 / antagonists & inhibitors*
  • Interleukin-4 / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology*
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Th2 Cells / cytology*
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism

Substances

  • Repressor Proteins
  • Interleukin-4
  • Immunoglobulin E
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases