Fong D C, Malbec O, Arock M, Cambier J C, Fridman W H, Daëron M
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO, USA.
Immunol Lett. 1996 Dec;54(2-3):83-91. doi: 10.1016/s0165-2478(96)02654-5.
We demonstrated previously that the low-affinity IgG receptors Fc gammaRIIB, which are coexpressed with the high-affinity IgE receptors Fc epsilonRI in mouse mast cells, can inhibit IgE-induced release of inflammatory mediators and cytokines by these cells. Inhibition was found to require the coaggregation of the two receptors and to depend on the presence of a tyrosine-based inhibition motif (ITIM) in the intracytoplasmic domain of Fc gammaRIIB. We report here that the coaggregation with Fc gammaRIIB does not prevent Fc epsilonRI from triggering activation signals in BMMC and induces the tyrosine phosphorylation of Fc gammaRIIB. Phosphorylated ITIM peptides bound in vitro to three SH2 domain-containing phosphatases present in BMMC lysates: the phosphotyrosine phosphatases SHP-1 and SHP-2. and the inositolphosphate phosphatase SHIP. Using BMMC generated from the SHP-1-deficient motheaten mice, SHP-1 was found to be dispensable for inhibition of mast cell activation. When analyzed for in vivo association, SHIP coprecipitated with phosphorylated Fc gammaRIIB, whereas SHP-1 or SHP-2 did not. These observations altogether indicate that Fc epsilonRI actively participates in its own regulation and that the mechanisms by which Fc gammaRIIB inhibit cell activation might be different in mast cells and in B-cells.
我们之前已证明，低亲和力IgG受体FcγRIIB与高亲和力IgE受体FcεRI在小鼠肥大细胞中共表达，它能够抑制这些细胞中IgE诱导的炎症介质和细胞因子释放。研究发现，抑制作用需要这两种受体的共聚集，并且依赖于FcγRIIB胞质结构域中基于酪氨酸的抑制基序（ITIM）的存在。我们在此报告，与FcγRIIB的共聚集并不妨碍FcεRI在骨髓来源的肥大细胞（BMMC）中触发激活信号，并且会诱导FcγRIIB的酪氨酸磷酸化。磷酸化的ITIM肽在体外与BMMC裂解物中存在的三种含SH2结构域的磷酸酶结合：磷酸酪氨酸磷酸酶SHP-1和SHP-2，以及肌醇磷酸磷酸酶SHIP。利用从SHP-1缺陷的motheaten小鼠产生的BMMC，发现SHP-1对于抑制肥大细胞激活并非必需。在分析体内关联时，SHIP与磷酸化的FcγRIIB共沉淀，而SHP-1或SHP-2则不会。这些观察结果共同表明，FcεRI积极参与其自身的调节，并且FcγRIIB抑制细胞激活的机制在肥大细胞和B细胞中可能有所不同。
