title: The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction.
abstract: Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+T cells.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Uruno
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shiraishi
authors.affiliation: Department of Functional Bioscience, Section of Infection Biology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0175, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Ushijima
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakahara
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Mayuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kido-Nakahara
authors.affiliation: Department of Pediatrics, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Tsuge
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.|Research Centre for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000276:immunology; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000276:immunology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D020662:Guanine Nucleotide Exchange Factors; D007073:Immunoglobulin E; D007378:Interleukins; D016329:Sp1 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse; C545324:Dock8 protein, mouse; C502588:interleukin-31, mouse