The inositol 5′-phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation and cytokine production

被引:41
作者
Leung, Wai-Hang [1 ]
Bolland, Silvia [1 ]
机构
[1] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA
关键词
D O I
10.4049/jimmunol.179.1.95
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Aggregation of the high-affinity IgE receptor (Fc epsilon RI) on mast cells initiates signaling pathways leading to degranulation and cytokine release. It has been reported that SHIP-1 negatively regulates Fc epsilon RI-triggered pathways but it is unknown whether its homologous protein SHIP-2 has the same function. We have used a lentiviral-based RNA interference technique to obtain SHIP-2 knockdown bone marrow-derived mast cells (BMMCs) and have found that elimination of SHIP-2 results in both increased mast cell degranulation and cytokine (IL-4 and IL-13) gene expression upon Fc epsilon RI stimulation. Elimination of SHIP-2 from BMMCs has no effect on Fc epsilon RI-triggered calcium flux, tyrosine phosphorylation of MAPKs or in actin depolymerization following activation. Rather, we observe that absence of SHIP-2 results in increased activation of the small GTPase Rac-1 and in enhanced microtubule polymerization upon Fc epsilon RI engagement. Coimmunoprecipitation experiments in rat basophilic leukemia (RBL 2H3) cells show that SHIP-2 interacts with the Fc epsilon RI beta-chain, Gab2 and Lyn and that unlike SHIP-1, it does not associate with SHC in mast cells. Our results report a negative regulatory role of SHIP-2 on mast cell activation that is calcium independent and distinct from the regulation by SHIP-1.
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页码:95 / 102
页数:8
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