Evidence for a regulatory loop between IFN-γ and IL-33 in skin inflammation.
Interleukin-33 has recently gained much attention due to its role in allergic responses. It has been shown to amplify Th2 responses and to act as a damage-associated molecular pattern. IL-33 acts on a broad range of cells and has been proposed to link innate and adaptive features of allergic responses. It was the aim of this study to investigate this property of IL-33 in the inflammatory response characterising atopic dermatitis (AD). We have analysed the response of skin-resident cells derived from patients with AD and healthy donors with regard to the expression of IL-33 and its receptor ST2. The functional impact of IL-33 on CD4+ T cells was investigated. Keratinocytes and dermal fibroblasts clearly differ in their regulation of IL-33. In fibroblasts, the concerted action of TNF-α and IL-1β was the strongest inducer, whereas IFN-γ is clearly the key molecule that upregulates IL-33 in keratinocytes with a more pronounced response of cells derived from patients with AD. Keratinocytes from patients with AD showed a markedly higher constitutive expression level of surface ST2. CD4+ T cells respond to IL-33. Unexpectedly, IL-33 failed to induce a significant secretion of IL-5 or IL-13. By contrast, high amounts of IFN-γ were detectable if IL-33 was added to the T-cell receptor-stimulated cells or in combination with IL-12. These results suggest that IL-33 and IFN-γ are closely interlinked in epidermal AD inflammation. IFN-γ induces IL-33 in keratinocytes and IL-33 acts on activated T cells to further increase the release of IFN-γ, therefore contributing to drive skin inflammation towards chronic responses.
Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. seltmann.jenny@mh-hannover.de
Jenny
J
Seltmann
Thomas
T
Werfel
Miriam
M
Wittmann
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000378:metabolism*; D004485:Eczema / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C506536:IL33 protein, human; D018793:Interleukin-13; D053583:Interleukin-1beta; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma