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| Dermatitis: Getting skin deep with IL-31
A newly identified and characterized cytokine, IL-31, may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases. Cytokines are part of a large family of secreted proteins that regulate a range of cellular functions — including proliferation, survival and maturation. Cytokines are essential mediators of the immune response and are implicated in a diverse set of diseases. Over 60 cytokines have been described so far, and now Dillon et al. report the discovery of yet another: interleukin 31 (IL-31), which is implicated in the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
Infiltrating T cells that persist in the skin, and the cytokines they produce, are thought to be involved in the development of pruritis and allergic and non-allergic conditions, including psoriasis and both atopic and non-atopic dermatitis (inflamed skin conditions). Cytokines mediate their functions through ligand-induced oligomerization of a dimeric receptor complex. A subset of cytokine receptors, classified as type 1, shows common structural features within the extracellular domain. Further classification shows a subfamily of type 1 receptors composed of gp130-related chains, which includes the oncostatin M receptor (OSMR) and the orphan receptor GLMR. By screening translated human genomic sequences for homologies to known cytokine receptor sequences, Dillon et al. identified four splice variants of a gp130-like type 1 cytokine receptor, IL-31RAv1 to IL-31RAv4, one of which is highly homologous to GLMR. Using a functional cloning approach, the cognate cytokine for at least two of the receptor splice variants, IL-31, was identified. IL-31 was secreted rapidly after TH2 cell activation, and the authors showed that it signals through a heterodimeric receptor composed of IL-31RA and OSMR that is expressed on both epithelial cells and keratinocytes. These cells responded to IL-31 stimulation and are likely to be involved in the dermatitis and pruritis observed in transgenic mice that overexpress IL-31. Similar pathologies were observed after systemic administration of IL-31 to wild-type mice, and mice deficient of IL-31RA are phenotypically normal and refractile to IL-31 administration. IL-31 stimulation induced a variety of chemokines, indicating that IL-31 may function in the recruitment of polymorphonuclear cells, monocytes and T cells to sites of skin inflammation in vivo. Furthermore, transgenic mice overexpressing IL-31 developed piloerection, followed by mild-to-severe alopecia (hair loss), and were also highly pruritic (itchy). Finally, Dillon et al. showed that IL-31 receptors were upregulated in lung epithelium and bronchoalveolar lavage cells derived from an animal model of airway hypersensitivity. The characterization of IL-31 by Dillon et al. suggests that this T cell-derived cytokine may be involved in promoting skin disorders and in regulating other allergenic diseases, such as asthma, adding this cytokine to the long list of known mediators of these conditions. Targeting IL-31 may prove to be an effective approach in the treatment of these diseases. Jon Reynolds, Copy Editor
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