title: ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.
abstract: In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63(lo/-)). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kamekura
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kumagai
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawata
authors.affiliation: Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mitsuhashi
authors.affiliation: Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoneta
authors.affiliation: Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sumikawa
authors.affiliation: Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Himi
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ichimiya
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000276:immunology* / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; C495344:TLR3 protein, human; C115051:TP63 protein, human; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000094632:Thymic Stromal Lymphopoietin