Elsevier

Cytokine

Volume 75, Issue 1, September 2015, Pages 57-61
Cytokine

Review Article
Mast cell production and response to IL-4 and IL-13

https://doi.org/10.1016/j.cyto.2015.05.019Get rights and content

Highlights

  • IL-4 & IL-13 play a prominent role in stimulating and maintaining allergic response.

  • IL-4 was the first cytokine shown to be made by mast cells.

  • IL-4Rα is the common IL-4 & IL-13 receptor subunit required for signal transduction.

  • Characterization of mouse versus human mast cell responses to IL-4 and IL-13.

  • Summary of the positive and negative roles IL-4 & IL-13 play in mast cell immunity.

Abstract

IL-4 was identified as the first cytokine to be produced by mast cells and is responsible for promoting mast cell IL-13 production. IL-4 and IL-13 play a prominent role in stimulating and maintaining the allergic response. As closely related genes, IL-4 and IL-13 share a common receptor subunit, IL-4Rα, necessary for signaling. Here we summarize the literature on mast cell activation associated with IL-4 and IL-13 production, including downstream signaling. We also describe the positive and negative roles each cytokine plays in mast cell immunity and detail the differences that exist between mouse and human mast cell responses 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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