Regulation of IL-33 expression by IFN-γ and tumor necrosis factor-α in normal human epidermal keratinocytes.
IL-33, a member of the IL-1 family, is implicated in type 2 T helper cell immune reactions and acts as an "alarmin" to induce activation of dendritic cells in response to external stimuli. We investigated the effect of inflammatory cytokines on IL-33 expression in normal human epidermal keratinocytes. IFN-γ dose- and time-dependently induced IL-33 expression in protein and mRNA; this was dependent on extracellular signal-regulated kinase, p38, EGFR, and JAK phosphorylation. Combined IFN-γ and tumor necrosis factor (TNF)-α treatment induced expression of a 20-kDa band corresponding to mature IL-33, which was abolished by the addition of a calpain inhibitor. The addition of the inhibitor to IFN-γ and TNF-α-stimulated cells also induced strong expression of a 25-kDa band. Small interference (si) RNA for IL-33 abolished expression of the smaller bands and the 30-kDa IL-33 band, suggesting that these IL-33 forms were IL-33 transcription products. Recombinant IL-33 added in the medium induced IL-8 production, and RNA knockdown by siRNA enhanced IL-8 expression, suggesting its dual role as a cytokine and a nuclear factor. These results indicate that IL-33 has a role in inflammatory skin diseases, in which IFN-γ and TNF-α are present in high levels.
Department of Dermatology, Jichi Medical University, Tochigi, Japan.
Jitlada
J
Meephansan
Hidetoshi
H
Tsuda
Mayumi
M
Komine
Shin-Ichi
S
Tominaga
Mamitaro
M
Ohtsuki
D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D052816:Foreskin / Q000166:cytology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D000067596:Interleukin-33; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008010:Lichen Planus / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference / Q000276:immunology; D012871:Skin Diseases / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology
C508606:CXCL8 protein, human; C506536:IL33 protein, human; D000067596:Interleukin-33; D016209:Interleukin-8; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D002154:Calpain