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J. Biol. Chem., Vol. 279, Issue 46, 48443-48448, November 12, 2004

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Impact of Engagement of FcRI and CC Chemokine Receptor 1 on Mast Cell Activation and Motility^*

Masako Toda, Maria Dawson, Takao Nakamura, Peter M. G. Munro, Ricardo Micheler Richardson¶, Maryse Bailly||, and Santa Jeremy Ono**

From the Division of Ocular Immunology, Clinical Ophthalmology, and ^||Cell Biology, Institutes of Ophthalmology, University College London, London EC1V 9EL, United Kingdom and the ^¶Department of Biochemistry, Meharry Medical College, Nashville, Tennessee 37208

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 FcRI-mediated signaling pathway affects degranulation positively but affects chemotaxis of mast cells adversely. Costimulation via FcRI 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, FcRI 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 FcRI 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 FcRI-mediated signaling pathway and CCR-mediated signaling pathway would induce optimal activation and arrested chemotaxis of mast cells, thus contributing to allergic inflammation.

Received for publication, July 30, 2004 , and in revised form, August 24, 2004.

^* This study was supported by National Institutes of Health Grants 1R01EY011901, 5R01EY012523, 7R01GM049661, and T32EY007156 and the Overseas Research Program from the Japan Society for the Promotion of Science (to M. T.). Santen Pharmaceutical Co. Ltd., GlaxoSmithKline Pharmaceutical PLC, and Fight for Sight (UK) also supported this research. The JEOL Model 6100 Scanning Electron Microscope was purchased with a bequest from the Leopold Muller Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: University College London, Institute of Ophthalmology, 11-43 Bath St., London EC1V 9EL, UK. Tel.: 44-20-7608-4069; Fax: 44-20-7608-4044; E-mail: santa.ono{at}ucl.ac.uk.

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