Identification of genes and proteins specifically regulated by costimulation of mast cell Fcε Receptor I and chemokine receptor 1.
ABSTRACT Mast cell function is a critical component of allergic reactions. Mast cell responses mediated by the high-affinity immunoglobulin E receptor FcεRI can be enhanced by co-activation of additional receptors such as CC chemokine receptor 1 (CCR1). To examine the downstream effects of FcεRI-CCR1 costimulation, rat basophilic leukemia cells stably transfected with CCR1 (RBL-CCR1 cells) were sensitized and activated with antigen and/or the CCR1 ligand CC chemokine ligand (CCL) 3. Gene and protein expression were determined at 3h and 24h post-activation, respectively, using GeneChip and Luminex bead assays. Gene microarray analysis demonstrated that 32 genes were differentially regulated in response to costimulation, as opposed to stimulation with antigen or CCL3 alone. The genes most significantly up-regulated by FcεRI-CCR1 costimulation were Ccl7, Rgs1, Emp1 and RT1-S3. CCL7 protein was also expressed at higher levels 24h after dual receptor activation, although RGS1, EMP1 and RT1-S3 were not. Of the panel of chemokines and cytokines tested, only CCL2, CCL7 and interleukin (IL)-6 were expressed at higher levels following costimulation. IL-6 expression was seen only after FcεRI-CCR1 costimulation, although the amount expressed was very low. CCL7, CCL2 and IL-6 might play roles in mast cell regulation of late-phase allergic responses.
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ABSTRACT: Mast cells (MC) are major participants in the allergic reaction. In addition they possess immunomodulatory roles in the innate and adaptive immune reactions. Their functions are modulated through a number of activating and inhibitory receptors expressed on their surface. This review deals with some of the most recently described receptors, their expression patterns, ligand(s), signal transduction mechanisms, possible cross-talk with other receptors and, last but not least, regulatory functions that the MC can perform based on their receptor expression in health or in disease. Where the receptor role on MC is still not clear, evidences from other hematopoietic cells expressing them is provided as a possible insight for their function on MC. Suggested strategies to modulate these receptors' activity for the purpose of therapeutic intervention are also discussed.Frontiers in Immunology 01/2012; 3:238. DOI:10.3389/fimmu.2012.00238
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ABSTRACT: Accumulating evidence points to cross-talk between FcεRI and CC chemokine receptor (CCR)-mediated signaling pathways in mast cells. Here, we propose that vimentin, a protein comprising type III intermediate filament, participates in such cross-talk for CCL2/monocyte chemotactic protein 1 (MCP-1) production in mast cells, which is a mechanism for allergic inflammation. Co-stimulation via FcεRI, using IgE/antigen, and CCR1, using recombinant CCL3/macrophage inflammatory protein-1α (MIP-1α), increased expression of phosphorylated, disassembled, and soluble vimentin in rat basophilic leukemia (RBL)-2H3 cells expressing human CCR1 (RBL-CCR1 cells) and bone marrow-derived murine mast cells, both models of mucosal type mast cells. Furthermore, co-stimulation enhanced production of CCL2 as well as phosphorylation of MAPK. Treating the cells with p38 MAPK inhibitor SB203580, but not with MEK inhibitor PD98058, reduced CCL2 production, suggesting that p38 MAPK, but not ERK1/2, plays a critical role in the chemokine production. Immunoprecipitation analysis showed that vimentin interacts with phosphorylated ERK1/2 and p38 MAPKs in the co-simulated cells. Preventing disassembly of the vimentin by aggregating vimentin filaments using β,β'-iminodipropionitrile reduced the interaction of vimentin with phosphorylated MAPKs as well as CCL2 production in the cells. Taken together, disassembled vimentin interacting with phosphorylated p38 MAPK could mediate CCL2 production in mast cells upon FcεRI and CCR1 activation.Journal of Biological Chemistry 05/2012; 287(29):24516-24. DOI:10.1074/jbc.M111.319624 · 4.60 Impact Factor
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ABSTRACT: Successful treatment of allergic eye disease depends on understanding the pathophysiology of ocular allergy. Thus, in this review, recent experimental and clinical research that has provided significant information about the immunopathology of allergic eye disease will be discussed. Recently, role of various cells, cytokines and chemokines has been scrutinized in the immunopathogenesis of ocular allergy. In this respect, current research highlights contribution of special molecules and cells in the development and clinical features of immunoglobulin E (IgE) and T-cell-mediated eye allergies. Recent findings in molecular immunology of ocular allergy, which comprise complex inflammatory conditions of the conjunctiva, have enabled us to better understand the pathophysiology of these diseases and have aided in the potential development of new therapeutic agents.Current Opinion in Allergy and Clinical Immunology 08/2012; 12(5):534-9. DOI:10.1097/ACI.0b013e328357a21b · 3.66 Impact Factor