Sensitized Mast Cells Migrate Toward the Agen: A Response Regulated by p38 Mitogen-Activated Protein Kinase and Rho-Associated Coiled-Coil-Forming Protein Kinase

Abstract

Although mast cells accumulate within the mucosal epithelial layer of patients with allergic rhinitis and bronchial asthma, the responsible chemotactic factors are undefined. We investigated whether mast cells sensitized with Ag-specific IgE migrate toward the Ag. MC/9 mast cells sensitized with anti-DNP IgE migrated toward DNP-conjugated human serum albumin. This migration was directional, and the degree was stronger than that induced by stem cell factor. IL-3 and stem cell factor-dependent cultured mast cells derived from mouse bone marrow also migrated toward the Ag. Subsequent migration mediated by the FcεRI was significantly inhibited by incubating the cells with Y-27632, a Rho-associated coiled-coil-forming protein kinase inhibitor, or with SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Both p38 MAPK and MAPK-activated protein kinase (MAPKAPK)2 were activated following FcεRI aggregation, and activation of MAPKAPK2 was almost completely inhibited by 10μM SB203580. Wortmannin or a low concentration of SB203580 partially inhibited MAPKAPK2, but did not block mast cell migration. In contrast, Y-27632 did not affect the activation of MAPKAPK2. These results indicate that Ag works not only as a stimulant for allergic mediators from IgE-sensitized mast cells, but also as a chemotactic factor for mast cells. Both p38 MAPK activation and Rho-dependent activation of Rho-associated coiled-coil-forming protein kinase may be required for FcεRI-mediated cell migration.

Btk-dependent Rac activation and actin rearrangement following FcεRI aggregation promotes enhanced chemotactic responses of mast cells

“…It has been reported that both IgE and IgEantigen induce mast-cell migration (Ishizuka et al, 2001;Jung et al, 2009;Kitaura et al, 2005), whereas another report noted that these responses might merely reflect chemokinesis or the autocrineparacrine action of chemotactic factors that are released from the activated mast cells (Kitaura et al, 2005;Taub et al, 1995). In the current study, we opted not to use fibronectin-coated membranes as used previously (Kitaura et al, 2005) to avoid the potential activation of integrin receptors that might augment chemotactic responses.…”

“…Others include several agonists of G-protein-coupled receptors (GPCRs), such as prostaglandin E 2 (PGE 2 ), which positively regulates mast-cell responses through the EP3 receptor (Weller et al, 2007). There is also evidence to suggest that IgEsensitized mast cells migrate toward antigen, potentially through the release of chemoattractants from mast cells themselves (Ishizuka et al, 2001;Kitaura et al, 2005). This evokes a potential contributory role for the high-affinity receptor for IgE (FcRI) in mast-cell homing, in addition to its role in release of the mast-cell mediator.…”

Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

“…These Rho-like G-proteins are known principally for their pivotal role in regulating the actin cytoskeleton in cell migration (Burridge and Wennerberg, 2004). PI3K has been thought to be a key molecule in the activation of cell migration through Rac signaling (Chandrasekar et al, 2003;van Leeuwen et al, 2003 Kawauchi et al, 2003) and p38MAPK (Rousseau et al, 1997;Cara et al, 2001;Ishizuka et al, 2001;Kimura et al, 2003;Pichon et al, 2004), have also been reported to be involved in cell migration. Consistent with these reports, our results indicate that activation of PI3K is required for the induction of glioma cell migration as well as for the activation of p38MAPK and JNK in response to LPA.…”

“…In prostate carcinoma cells (Edlund et al, 2002), Cdc42 as well as RhoA could participate in not only transforming growth factor-binduced formation of stress fibers but also in membrane ruffling. It has been shown that p38MAPK, MAPKKAPKs and hsp25/27 might be involved in polymerization of actin (Ishizuka et al, 2001). Recent finding has also shown that JNK phosphorylates paxillin, and suggested that phosphorylation of actin-associated adaptor proteins for focal adhesion is a possible mechanism through which JNK affects the organization of actin cytoskeleton and the migration of epithelial cells .…”

Stem Cell Factor Has a Suppressive Activity to IgE-Mediated Chemotaxis of Mast Cells

“…Much is known that cross-linking of IgE bound to Fc⑀RI by specific Ag mediates rapid release of biologically active chemical mediators and production of proinflammatory cytokines. Recently, IgE binding to the mast cell surface has been reconfirmed to mediating directional migration toward IgE-specific Ag (20,21). Moreover, monomeric IgE up-regulates Fc⑀RI expression and induces survival and cytokine production of mast cells (22)(23)(24).…”