title: Extracellular double-stranded RNA induces TSLP via an endosomal acidification- and NF-κB-dependent pathway in human keratinocytes.
abstract: Double-stranded RNA (dsRNA) causes keratinocytes to release thymic stromal lymphopoietin (TSLP), which plays a key role in allergic diseases. Endosomal Toll-like receptor 3 (TLR3) and cytosolic RIG-like receptors (RLRs) and PKR have been reported to recognize dsRNA. Here, we demonstrate that dsRNA induces TSLP in keratinocytes via an endosomal acidification-dependent and NF-κB-mediated pathway. After treatment with pharmacologic inhibitors or transfection with small interfering RNAs (siRNAs), primary human keratinocytes were stimulated. Bafilomycin A1, which inhibits endosomal acidification to block the TLR3 pathway, blocked the dsRNA-induced expression of TSLP, IL-8, IFN-β, and other molecules including the dsRNA sensors, whereas it did not inhibit diacyllipopeptide-induced expression of TSLP and IL-8. The dsRNA-induced gene expression of TSLP depended on RelA, a component of NF-κB, but not IRF3, similar to IL-8 but different from IFN-β, which depended on both IRF3 and RelA. The results indicate that endosomal acidification and the subsequent activation of NF-κB are necessary to sense extracellular dsRNA, suggesting the importance of the TLR3-NF-κB axis to trigger production of TSLP against the self dsRNA released from damaged cells or viral dsRNA, in the epidermis, relating to skin inflammation including atopic dermatitis (AD).
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Anh T
authors.initials: AT
authors.lastname: Vu
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Seiji
authors.initials: S
authors.lastname: Kamijo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushio
authors.forename: Junko
authors.initials: J
authors.lastname: Kawasaki
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Hara
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Toshiro
authors.initials: T
authors.lastname: Takai
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D000078183:Oxindoles; D011070:Poly I-C / Q000494:pharmacology; D011422:Propionates; D011758:Pyrroles / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; C494232:IRF3 protein, human; D007211:Indoles; D050838:Interferon Regulatory Factor-3; D016209:Interleukin-8; D018942:Macrolides; D016328:NF-kappa B; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051996:Transcription Factor RelA; D016899:Interferon-beta; C040929:bafilomycin A1; C412603:orantinib; D011070:Poly I-C; D000094632:Thymic Stromal Lymphopoietin