Reprogramming of mast cells to induce a hypoactive phenotype through prolonged SCF exposure

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIAID	IMMUNO/INFLAM-10

Authors

• T Ito
• D Smrz
• H Kuehn
• S Smrzova
• G Bandara
• M Jung
• A Desai
• M Beaven
• D Metcalfe
• A Gilfillan

Abstract

In response to antigen, mast cells (MC) release an array of mediators that contribute to allergic disorders. Acute exposure to KIT ligand (stem cell factor; SCF), produces marked potentiation of the antigen-mediated response. However, the manifestations of extended exposure to SCF that likely occurs in vivo is unknown. In investigating this issue, we identified a novel mechanism for the inhibition of MC mediator release through phenotypic reprogramming by SCF. Mouse bone marrow-derived MC (BMMC) developed in media containing IL-3 and chronically exposed to SCF displayed a marked attenuation of FcepsilonRI-mediated degranulation and cytokine production. Once induced, this phenotype was not readily reversed by removal of SCF. These effects were not due to impaired activation of PLCgamma, PI3K, PKC, and MAPK, nor to defective calcium mobilization. However, as revealed by gene expression microarray, and confirmed by immunoblot analysis, the hyporesponsive phenotype may be explained by down-regulation of expression of Hck, a critical mast cell signaling molecule. Collectively, these data provide evidence that mast cells can be reprogrammed by SCF to produce a hyporesponsive phenotype. As such, these findings may have important ramifications for the development of novel approaches for the treatment on MC-driven diseases.

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