The Mediators Expressed by Mast Cells and Their Role in the Inflammatory Response

Plaut et al. (45) first demonstrated that murine mast cells were capable of expressing many cytokines. Since then, we and others have shown that human mast cells express a spectrum of cytokines and chemokines (3,46,47). Both in vivo and in vitro studies have shown that human mast cells are capable of expressing pleiotropic cytokines and growth factors, such as TNF-a (3,4851), granulocyte macrophage colony-stimulating factor (52), IL-3 and IL-4 (36,53-59), IL-5 (54-56,60), IL-6 (55,56,61-64), IL-8 (54,65,66), IL-10 (67), IL-13 (68-70), IL-16 (71), MIP-1 a (72), MIP-1 p (73), regulated upon activation normal T-cell-expressed and -secreted (3,73), and MCP-1 (74,75). Human mast cells also are capable of expressing growth factors. Vascular endothelial growth factor (VEGF), a cytokine crucial to angiogenesis and the growth of blood vessels, and NGF (76,77), are recognized products of mast cells. Autocrine production of SCF has been shown from mast cells (78,79).

It is likely that heterogeneity of human mast cells exists in regards to cytokine expression in vivo and studies by Bradding et al. (63), demonstrated this phenomenon in mast cells obtained from bronchial biopsies of patients suffering from asthma. By immunocytochemistry, these investigators noted that although MCtc cells predominantly expressed IL-4, the MCtc cells expressed both IL-5 and IL-6 (63). In our studies, cord blood-derived mast cells expressed the eosinophil-active growth factors IL-5 and GM-cSF and the eosinophil chemotactic C-X-C chemokine, IL-8, after activation (42). The production of these cytokines in cord blood-derived mast cells was further enhanced by the addition of the monokines IL-1P and TNF-a in a dose-dependent manner while dexamethasone inhibited production of these cytokines. How these various cytokines and chemokines interact with the inflammatory response is summarized below.

Mast cells have been incriminated in such diverse diseases as allergy, asthma, rheumatoid arthritis, atherosclerosis, interstitial cystitis, inflammatory bowel disease, progressive systemic sclerosis, chronic graft-vs-host disease, fibrotic diseases, sarcoidosis, asbestosis, ischemic heart disease, keloid scars, and malignancy (3). The mediators released by mast cells can independently and, in synergy with macrophage- and T-cell-derived cytokines, induce much of the inflammatory pathology observed in inflammation and serve to orchestrate a complex immune response. Histamine, LTB4, LTC4, PAF, and PGD2 may have multiple effects on inflammatory cell recruitment (eosinophils), smooth muscle hyperplasia, and vascular dilatation (80,81). Tryptase, chymase, and TNF-a from mast cells activate fibroblasts, leading to collagen deposition and fibrosis. Mast cell-derived TNF-a regulates NF-KB-dependent induction of endothelial adhesion molecule expression on endothelial cells in vivo (49). Mast cell granules and tryptase also can potentiate endotoxin-induced IL-6 production by endothelial cells. Mast cell-derived cytokines and chemokines further regulate IgE synthesis and cell migration, basophil histamine release, smooth muscle proliferation, and endothelial chemotaxis and proliferation. IL-4 and IL-13 can regulate adhesion molecule expression on endothelial cells but also can class switch B cells to synthesize IgE (82,83). Data suggest that mast cells also can directly activate B cells to switch to IgE. IL-5, another product of mast cells, also can serve to activate eosinophils while accentuating IgA production from B cells. Chemokines (such as IL-8) and leukotrienes (specifically LTC4) released by mast cells can recruit neutrophils and eosinophils to inflamed airways, which can further potentiate damage (3). Mast cells also have been postulated to provide the IL-4 pulse that allows the development of Th2 cells that

Mast Cells And Eosinophilic Disease
Fig. 4. Multiple roles of human mast cells in chronic disease states and immunophysiology or pathology.

selectively secrete IL-4 and IL-5 on activation (84). Exciting recent data also suggest that certain mast cell-derived chemokines, especially MIP-1a, can potentiate a shift of T cells towards a Thl-phenotype, whereas others, such as MCP-1, can shift these cells functionally to a Th2-phenotype (85). Thus, T cells and mast cells can complement the functions of each other and contribute to the "cytokine pool" that leads subsequently to chronic inflammation.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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