ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of Fcɛ receptor I-mediated activation of Syk

Abstract

Engagement of the mast cell high-affinity receptor for immunoglobulin E (IgE) Allergen-induced activation of the high-affinity receptor for IgE (FcRI) in mast cells and basophils plays a pivotal role in the initiation of allergic and inflammatory reactions. As a result of receptor engagement, mast cells and basophils release a variety of inflammatory mediators, such as histamine, arachidonic acid metabolites, and cytokines (1, 2). The activation of protein tyrosine kinases (PTKs) is one of the early and critical signaling events following FcRI engagement (3). Since FcRI belongs to the family of multisubunit antigen receptors that do not possess intrinsic PTK activity in their structure (1), the recruitment and activation of non-receptor PTKs is crucial for FcRI-mediated signal transduction (4).,FcRI is a tetrameric receptor composed of an ␣ subunit, a ␤ subunit, and a homodimer of disulfide-linked ␥ subunits (5). The cytoplasmic domains of ␤ and ␥ subunits contain sequences known as the immunoreceptor tyrosine-based activation motifs (ITAMs) (6, 7). The phosphorylation of the tyrosines of the ITAM allows the interaction of ITAMcontaining receptors with signaling proteins that have phosphotyrosine-recognizing Src homology 2 (SH2) domains (8, 9).

Tyrosine phosphorylation-dependent and -independent associations of protein kinase C-Δ with Src family kinases in the RBL-2H3 mast cell line: regulation of Src family kinase activity by protein kinase C-δ

“…This is consistent with prior studies on the localization of tyrosine phosphorylated PKC-d (Li et al, 1994b;Haleem-Smith et al, 1995;Solto and Toker, 1995;Denning et al, 1996). Furthermore, we found that the Syk-selective inhibitors, piceatannol and ER-27319, had neither an eect on the tyrosine phosphorylation of PKC-d nor on the activity of Lyn (data not shown and Moriya et al, 1997). Collectively the results exclude mast cell tyrosine kinases, like Syk and Bruton's tyrosine kinase (BTK, Kawakami et al, 1996), that are recruited to the membrane in response to FceRI engagement.…”

Multiple Defects in FcεRI Signaling in Syk-Deficient Nonreleaser Basophils and IL-3-Induced Recovery of Syk Expression and Secretion

“…Rather, Ag-stimulated basophils release mediators that induce both acute and late phase allergic responses; they are major sources of IL-4 and IL-13, key cytokines in the propagation of allergic inflammation, and there is a strong relationship between clinical improvement induced by anti-IgE immunotherapy and reduced Fc⑀RI-mediated basophil degranulation (17,26,27). In rodent models, all methods to eliminate Syk, use of Syk-selective inhibitors (28,29), of Syk-negative cell lines (30), of cells from Syk knockout mice (31), and by use of Syk antisense oligonucleotides (32) have consistently eliminated most or all Fc⑀RI signaling responses. However, human allergy is unlikely to be easily treated with Syk inhibitors because this kinase is essential for many other functions, including the development and function of T cells, B cells, and platelets (20,33).…”

Mycobacteria-Infected Dendritic Cells Attract Neutrophils That Produce IL-10 and Specifically Shut Down Th17 CD4 T Cells through Their IL-10 Receptor

“…We investigated whether these pathways were also involved in IL-10 production after contact between BCG-infected DCs and neutrophils. Treatment of BCG-DC-neutrophil cocultures with the two Syk inhibitors, piceatannol and ER27319 (39,40), substantially reduced IL-10 secretion (Fig. 3A).…”