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.
Highlights
CC chemokine ligand 2 (CCL2) recruits leukocytes in inflammatory tissues
CCL2 Production and mitogen-activated protein kinase (MAPK) Activation Are Enhanced in Fc⑀RI- and chemokine receptor 1 (CCR1)-activated rat basophilic leukemia (RBL)-CCR1 Cells—CCL2 plays a critical role in activation and accumulation of leukocytes in allergic inflammatory tissues [3, 7,8,9, 15]
This CCL2 production was attenuated by the p38 MAPK inhibitor SB203580 (Fig. 1B) but not by the MEK inhibitor PD98058, which inhibits activation of extracellular signal-regulated kinase 1/2 (ERK1/2) (Fig. 1C). These results suggest that p38 MAPK but not ERK1/2 kinase plays a role in Fc⑀RI- and CCR1-mediated CCL2 production in RBL-CCR1 cells
Summary
CC chemokine ligand 2 (CCL2) recruits leukocytes in inflammatory tissues. Results: Vimentin, a cytoskeletal protein, interacted with phosphorylated MAPKs, was critical for CCL2 production in mast cells activated via F⑀cRI and a CC chemokine receptor. A superfamily of small, structurally related cytokine molecules, chemokines are characterized by their ability to affect trafficking of leukocytes Some chemokines, such as CCL2/MCP-1 (monocyte chemotactic protein 1), CCL3/MIP-1␣ (macrophage inflammatory protein-1␣), CCL5/RANTES (regulated upon activation, normal T-cell expressed and secreted), and CCL11/eotaxin-1, have been reported to activate mouse, rat, or human mast cells [3,4,5,6]. CCL3 synergistically enhanced Fc⑀RI-mediated degranulation and gene expression of cytokines and chemokines (e.g. IL-6 and CCL7/MCP-3) in a rat basophilic leukemia 2H3 cell line (RBL-2H3) expressing CC chemokine receptor 1 (CCR1), a receptor for CCL3, and bone marrow-derived murine mast cells [11,12,13,14] These observations indicate that (i) the simultaneous engagement of Fc⑀RI and CCR1 is important for optimal activation of mast cells in vitro and physiologically relevant levels of mast cell activation in vivo, and (ii) there is a cross-talk between the Fc⑀RI-mediated and CCR1-mediated signaling cascades. Our findings suggest that vimentin is a component for optimal production of CCL2 in the Fc⑀RI- and CCR1-engaged mast cells
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