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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2059-2065.
Prepublished online as a Blood First Edition Paper on November 12, 2004; DOI 10.1182/blood-2004-07-2639.
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IMMUNOBIOLOGY
Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen
Masayuki Kohno,
Sho Yamasaki,
Victor L. J. Tybulewicz, and
Takashi Saito
From the Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan; Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa, Japan; and Division of Immune Cell Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.
Cross-linking Fc RI on mast cells by immunoglobulin E (IgE) and antigen (Ag) initiates cascades leading to antiparasitic or allergic responses. It was recently reported that IgE without antigen, IgE(-Ag), actively promotes mast cell survival. Although we have demonstrated that the immunoreceptor tyrosine-based activation motif within FcR is essential for IgE(-Ag)–induced mast cell survival, the underlying mechanism remains still unclear. Here, we investigated the mechanism of IgE(-Ag)–induced survival using mast cells lacking several downstream molecules. Lyn and Syk were essential, whereas Fyn, Gab2, and the phosphoinositide 3-kinase–Akt pathway were not critical for survival. Failure of survival in FcR-/- bone marrow mast cells (BMMCs) was rescued by coculture with IgE-treated wild-type BMMCs, suggesting that survival is induced not directly through FcRI signals. We found that the survival is predominantly mediated by high production of interleukin 3 (IL-3), evidenced by severe impairment of survival by anti–IL-3 and in IL-3-/- BMMCs. The up-regulation of Bcl-xL/Bcl-2 by IgE was abrogated in IL-3-/- BMMCs, whereas the expression of histidine decarboxylase was normally induced. These results indicate that IL-3 plays a crucial role for IgE(-Ag)–induced mast cell survival, functioning in an autocrine manner by inducing the Bcl-xL/Bcl-2 via signal transducer and activator of transduction 5. We further suggest that IgE(-Ag)–mediated gene expression in mast cells is regulated at least 2 mechanisms: autocrine IL-3 dependent and independent.
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