Mast Cell Activation and Mediator Production

Human mast cells and basophils express the receptor for IgE, FceRI (2). FceRI (in contrast to the other receptor for IgE, FceRII) binds IgE with high affinity (22). The other receptor for IgE, FceRII, has been detected on eosino-

phils, mononuclear cells, lymphocytes, and platelets. FceRI is a multimeric complex composed of four chains, designated as a (which has the IgE-binding domain), P, and the two disulfide-linked y chains (23,24). Typically, multivalent antigen binds to IgE, which in turn binds by the Fc portion to the a-chain of FceRI, leading subsequently to receptor aggregation and internalization and culminating in receptor-mediated signaling. The P and y chains of FceRI possess the immune receptor tyrosine-based activation motifs, which are considered pivotal to signal transduction (25). The bridging of two IgE molecules by multivalent antigen or by univalent antigen in presence of a carrier molecule results in activation of Lyn kinase, which then phosphorylates the P and y chains (22). The absence of Lyn has been associated with defective mast cell signaling in mice (26). Syk kinase then becomes activated sequentially, followed by involvement of phospholipase C y mitogen-activated protein kinases (MAPK), and phosphoinositol-3 kinase (27). The generation of inositol triph-osphate and of diacylglycerol and other second messengers leads to release of calcium intracellularly as well as protein kinase C activation, events culminating in FceRI-mediated secretion. Degranulation appears to be associated with activation of G proteins that cause actin polymerization and relocalization. These events also are accompanied by the transcription of several cytokine genes, leading to further evolution of the inflammatory cascade.

In a typical allergic reaction, antigen/allergen (for example, latex or peanut allergen) crosslinks two IgE molecules occupying FceRI, resulting in a cascade of rapid sequence signaling events and leading to degranulation and elaboration of mediators (28). Mast cells also can be activated to degranulate by a variety of stimuli including; opiates, components of the complement cascade (29-31), neuropeptides (vasoactive intestinal peptide, calcitonin gene-related peptide, and substance P), superoxide anion, radio-contrast media, oxidized low-density lipoproteins, histamine releasing factors, chemokines (monocyte chemotactic proteins-1, -2, and -3 [MCP-1, -2, -3], and monocyte inflammatory peptide 1 a [MIP-1 a]), regulated upon activation normal T-cell-expressed and secreted (RANTES), connective tissue-activating peptide, pathogenic bacteria (32,33), parasites (34,35), enterotoxin B (36), cholera toxin (37), or changes in osmolality (38,39). We have recently demonstrated that IL-1, catecholamines, and cell-cell interactions (e.g., mast cell-fibroblast contact) can enhance mast cell activation and cytokine expression (40-43), which indicates the occurrence of multiple pathways of mast cell activation.

Mediators secreted by mast cells can be subdivided into preformed (secretory granule-associated) and others newly synthesized after cellular activation (3,44). Preformed mediators (summarized in Fig. 3) include histamine, proteoglycans (heparin, chondroitin sulfate E), serotonin, proteases (such as tryptase, chymase, P-hexosaminidase, P-glucuronidase, P-D-galactosidase, cathepsin G,

FctRl + IgE+Antigen

New Synthesis TNF-a Chemokines •IL-8/ENA-78 • MCP-1 /RANTES •MIP-1 a TGF-ß

_ Mast cell

Inflammation •Vascular injury •Cell recruitment •Cell adhesion • Remodel ing/fibrosis •Angiogenesis

Granule release:

Histamine, PAF Eicosanoids Neutral proteases Cytokines

Fig. 3. After activation of mast cells by IgE and antigen, the release of preformed and newly synthesized mediators occurs, leading to acute and chronic inflammatory effects, mediated by vascular injury, cellular recruitment, and culminating in tissue remodeling and angiogenesis.

and carboxypeptidase), some cytokines (tumor necrosis factor [TNF]-a), and basic fibroblast growth factor (bFGF). The newly generated products include the lipid mediators (prostaglandin D2 and leukotrienes, generated from arachidonic acid), thromboxanes, 5,12-hydroxy-eicosatetraenoic acid, nitrogen radicals, oxygen radicals, inflammatory cytokines, and several chemokines.

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