title: TSLP Down-Regulates S100A7 and ß-Defensin 2 Via the JAK2/STAT3-Dependent Mechanism.
abstract: Elevated T-helper type 2 cytokines in atopic skin, such as IL-4 and IL-13, were thought to be responsible for an impaired expression of antimicrobial proteins, which may contribute to the increased susceptibility to skin infections in patients with atopic dermatitis. In this study, the relationship between thymic stromal lymphopoietin and antimicrobial proteins and the involved molecular pathway was defined in normal human epidermal keratinocytes and human skin equivalent model. Stimulation of normal human epidermal keratinocytes with thymic stromal lymphopoietin decreased both mRNA and levels of S100A7 and human β-defensin 2 in a dose-dependent manner, and the regulation was JAK2/STAT3-dependent. Thymic stromal lymphopoietin decreased the antimicrobial protein expression, even in the presence of IL-17, which is their strong inducer. STAT3 directly regulated the S100A7 and human β-defensin 2 promoters in normal human epidermal keratinocytes. Immunohistochemically, lesional atopic skin stained more intensely with phospho-STAT3 compared with healthy control. Our results show that up-regulated thymic stromal lymphopoietin may contribute to the deficiency of antimicrobial proteins in atopic dermatitis, including S100A7 and human β-defensin 2, by a JAK2/STAT3-dependent mechanism and that STAT3/Sin3a might directly control the transcriptional activity of the antimicrobial protein promoters in normal human epidermal keratinocytes. Taken together, a key role of the JAK2/STAT3/Sin3a signaling pathway in thymic stromal lymphopoietin-mediated immune response in normal human epidermal keratinocytes might give us clues to understanding the pathological signal transductions in atopic dermatitis.
authors: Department of Dermatology and Division of Brain, Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Hana
authors: H
authors: Lee
authors: Department of Dermatology and Division of Brain, Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Woo-In
authors: WI
authors: Ryu
authors: Department of Dermatology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: Hee Joo
authors: HJ
authors: Kim
authors: Department of Dermatology and Division of Brain, Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Hyun Cheol
authors: HC
authors: Bae
authors: Department of Dermatology and Division of Brain, Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Hwa Jung
authors: HJ
authors: Ryu
authors: Department of Dermatology and Division of Brain, Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Jung Jin
authors: JJ
authors: Shin
authors: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea; Department of Biochemistry, Korea University College of Medicine, Seoul, Korea; Division of Brain, Korea 21 Program for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Kwon-Ho
authors: KH
authors: Song
authors: Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea; Department of Biochemistry, Korea University College of Medicine, Seoul, Korea; Division of Brain, Korea 21 Program for Biomedical Science, Korea University College of Medicine, Seoul, Korea.
authors: Tae Woo
authors: TW
authors: Kim
authors: Department of Dermatology and Division of Brain, Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, Korea. Electronic address: skin4u@korea.ac.kr.
authors: Sang Wook
authors: SW
authors: Son
mesh_terms: D001707:Biopsy, Needle; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D016207:Cytokines / Q000494:pharmacology*; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000187:drug effects / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D050796:STAT3 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D000094632:Thymic Stromal Lymphopoietin