The role of SHIP in mast cell degranulation and IgE-induced mast cell survival.
Atopic disorders are on the increase in the Western world and are due, at least in part, to an overactive mast cell response. A better understanding of the intracellular signalling pathways that regulate both mast cell degranulation and the secretion of arachidonic acid metabolites and inflammatory cytokines could help in the treatment of these disorders. The src homology 2-containing inositol-polyphosphate 5'-phosphatase, SHIP, has been shown to be a key 'gatekeeper' of mast cell degranulation. SHIP prevents degranulation from occuring when IgE alone binds to the high-affinity receptor for IgE (FcvarepsilonR1), SHIP restrains it when IgE-bound FcvarepsilonR1 are engaged by multivalent allergens, and SHIP inhibits it when an IgG against the same allergen co-clusters the inhibitory low-affinity receptor for IgG (FcgammaRIIB) with the IgE receptor. SHIP acts as a negative regulator of degranulation by hydrolyzing phosphatidylinositol-3,4,5-trisphosphate, a second messenger generated in activated cells by phosphatidylinositol 3-kinase. Our finding that binding of only IgE to the FcvarepsilonR1 of SHIP-deficient mast cells results in massive degranulation, led us to investigate the signalling pathways that are triggered in normal murine bone marrow-derived mast cells by monomeric IgE. We report here that monomeric IgE activates signalling pathways resulting in mast cell survival, without stimulating degranulation or proliferation. These studies demonstrate that mast cell sensitization by IgE is an active rather than a passive process.
Huber
Michael
M
Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany. huberm@immunbio.mpg.de
Kalesnikoff
Janet
J
Reth
Michael
M
Krystal
Gerald
G
D000818:Animals; D015550:Cell Degranulation; D002470:Cell Survival; D002478:Cells, Cultured; D007073:Immunoglobulin E / Q000494:pharmacology*; D007700:Kinetics; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D007073:Immunoglobulin E; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases