Review ArticleMast cell production and response to IL-4 and IL-13
Section snippets
Introduction: Mast cell function overview
Mast cells develop from hematopoietic progenitors but complete their maturation in peripheral tissues. They are widely distributed throughout most tissues, especially at the mucosal interface [1], [2], [3]. Due to their location at the interface between the host and the external environment and their expression of Toll-like receptors that recognize bacterial components, mast cells are known for their role as first-line defenders against invading pathogens [4], [5], [6], [7], [8], [9], [10], [11]
Mast cells produce IL-4 and IL-13
Mast cell cytokine secretion plays a pivotal role in the pathogenesis of allergic disease and inflammation [16]. Among the cytokines produced by human and mouse mast cells are IL-4 and IL-13. In fact, IL-4 was the first cytokine shown to be made by mast cells, in 1987 [4], [17], [18], [19], [20]. Mast cell IL-4 production has been best studied in relation to IgE-mediated activation [4], however it can also be produced in response to IL-33 [1], [2], [3], [21] and lectins [4], [5], [6], [7], [8],
Regulating IL-4 and IL-13 production
Due to its critical role in determining the nature of immune responses, the regulatory pathways eliciting IL-4 production have been extensively studied. While IL-4 is most widely recognized for mediating Th2 cell differentiation and thus antibody-driven immune responses, there are similarities and differences in the pathways utilized for TCR versus IgE-mediated IL-4 secretion. The Th2-specific transcription factor c-maf has been shown to be responsible for activating the IL-4 promoter and
Effects of IL-4 and IL-13 on mast cells: allergy and infection models
IL-4 and IL-13 are closely related genes. The IL-4 and IL-13 receptors share a common subunit (IL-4Rα) required for signal transduction. IL-4Rα paired with IL-13Rα1 can be activated by IL-13 or IL-4. In contrast, IL-4Rα paired with the common gamma chain is only activated by IL-4 [42]. In an allergic model, IL-4 and IL-13 act on the vasculature, sensitizing toward histamine, platelet activating factor (PAF), or leukotriene C4 (LTC4), and enhancing mast cell-mediated anaphylaxis [43]. A key
Effects of IL-4 and IL-13 on mast cells: differences between human and mouse systems
While mast cells produce IL-13, their ability to respond to IL-13 has been sparsely reported. To identify gene expression differences between IL-4 and IL-13, the Nilsson group studied the HMC-1 mast cell line and primary human cord blood mast cells. IL-13 induced c-fos expression, up-regulated ICAM-1 (CD54), and decreased c-kit expression. IL-4 elicited the same genes, but with greater potency [44]. Both cytokines suppressed HMC-1 proliferation, while only IL-4 altered cord blood mast cell
Importance of mast cell IL-4 and IL-13
While mast cells produce IL-4 and IL-13, the essential role of these cytokines strictly from this source has not been widely investigated. This is in contrast to mast cell-derived TNF, which has been examined in several contexts. The common approach is to reconstitute c-Kit-mutant mice, which lack mast cells, with wild type or gene-deficient mast cells, generating a mast cell-restricted knockout mouse. Reconstituting mast-cell deficient mice with TNF−/− mast cells, researchers found that IL-33
Summary
Mast cells are potent sources of cytokines, able to respond to a myriad of stimuli. Their production and responsiveness to IL-4 and IL-13 is important to our understanding of allergic and inflammatory diseases. Particularly in diseases such as allergic asthma, targeting mast cell-derived cytokines may prove extremely beneficial. Currently this is done by broadly suppressive drugs, such as corticosteroids. Targeted approaches offer hope for selective therapy with fewer side effects.
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