Toda Masako, Dawson Maria, Nakamura Takao, Munro Peter M G, Richardson Ricardo Micheler, Bailly Maryse, Ono Santa Jeremy
Division of Ocular Immunology, Institutes of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
J Biol Chem. 2004 Nov 12;279(46):48443-8. doi: 10.1074/jbc.M408725200. Epub 2004 Aug 26.
CC chemokines participate in the recruitment and activation of immune cells through CC chemokine receptors (CCRs). Here, we report that cross-talk between CCR1-mediated signaling pathway and FcepsilonRI-mediated signaling pathway affects degranulation positively but affects chemotaxis of mast cells adversely. Costimulation via FcepsilonRI engagement with IgE/antigen and CCR1 engagement with recombinant human CCL3 synergistically enhanced degranulation in rat basophilic leukemia-2H3 cells expressing human CCR1 (RBL-CCR1). Interestingly, FcepsilonRI engagement inhibited CCL3-mediated chemotaxis and membrane ruffling of RBL-CCR1 cells. Small GTP-binding proteins of the Rho family, Rac, Cdc42, and Rho control chemotaxis by mediating the reorganization of the actin cytoskeleton. Both a Rho inhibitor C3 exoenzyme and a Rho kinase (ROCK) inhibitor Y-27632 inhibited chemotaxis of RBL-CCR1 cells toward CCL3, indicating that activation of the Rho/ROCK signaling pathway is required for the CCL3-mediated chemotaxis of the cells. Costimulation with IgE/antigen and CCL3 enhanced Rac and Cdc42 activation but decreased ROCK activation in RBL-CCR1 cells compared with that in the cells stimulated with CCL3 alone. These results suggest that costimulation via FcepsilonRI and CCR1 engagements induced 1) inhibition of membrane ruffling, 2) decreased ROCK activation, and 3) reciprocal imbalance between Small GTP-binding proteins of the Rho family, which result in the inhibition of chemotaxis of RBL-CCR1 cells. The cross-talk between FcepsilonRI-mediated signaling pathway and CCR-mediated signaling pathway would induce optimal activation and arrested chemotaxis of mast cells, thus contributing to allergic inflammation.
CC趋化因子通过CC趋化因子受体（CCR）参与免疫细胞的募集和激活。在此，我们报道CCR1介导的信号通路与FcepsilonRI介导的信号通路之间的相互作用对脱颗粒有正向影响，但对肥大细胞的趋化性有不利影响。通过FcepsilonRI与IgE/抗原结合以及CCR1与重组人CCL3结合进行共刺激，可协同增强表达人CCR1的大鼠嗜碱性白血病-2H3细胞（RBL-CCR1）的脱颗粒。有趣的是，FcepsilonRI结合抑制了RBL-CCR1细胞的CCL3介导的趋化性和膜皱襞形成。Rho家族的小GTP结合蛋白Rac、Cdc42和Rho通过介导肌动蛋白细胞骨架的重组来控制趋化性。Rho抑制剂C3外切酶和Rho激酶（ROCK）抑制剂Y-27632均抑制RBL-CCR1细胞对CCL3的趋化性，表明Rho/ROCK信号通路的激活是细胞CCL3介导的趋化性所必需的。与单独用CCL3刺激的细胞相比，用IgE/抗原和CCL3进行共刺激可增强RBL-CCR1细胞中Rac和Cdc42的激活，但降低ROCK的激活。这些结果表明，通过FcepsilonRI和CCR1结合进行共刺激可诱导：1）膜皱襞形成的抑制；2）ROCK激活的降低；3）Rho家族小GTP结合蛋白之间的相互失衡，从而导致RBL-CCR1细胞趋化性的抑制。FcepsilonRI介导的信号通路与CCR介导的信号通路之间的相互作用会诱导肥大细胞的最佳激活和趋化性停滞，从而导致过敏性炎症。
