title: Critical role for mast cell Stat5 activity in skin inflammation.
abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Here, we show that phospholipase C-β3 (PLC-β3)-deficient mice spontaneously develop AD-like skin lesions and more severe allergen-induced dermatitis than wild-type mice. Mast cells were required for both AD models and remarkably increased in the skin of Plcb3(-/-) mice because of the increased Stat5 and reduced SHP-1 activities. Mast cell-specific deletion of Stat5 gene ameliorated allergen-induced dermatitis, whereas that of Shp1 gene encoding Stat5-inactivating SHP-1 exacerbated it. PLC-β3 regulates the expression of periostin in fibroblasts and TSLP in keratinocytes, two proteins critically involved in AD pathogenesis. Furthermore, polymorphisms in PLCB3, SHP1, STAT5A, and STAT5B genes were associated with human AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels of phospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ando
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Siavash
authors.initials: S
authors.lastname: Namiranian
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tomimori
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Hong
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Miho
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Laboratory for Allergic Disease, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama 230-0045, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kashiwakura
authors.affiliation: Division of Dermatology, Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA.
authors.forename: Tissa R
authors.initials: TR
authors.lastname: Hata
authors.affiliation: Division of Medical Biochemistry, Department of Biomolecular Sciences and Department of Laboratory Medicine, Saga Medical School, Saga 849-85-01, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gurish
authors.affiliation: Institute for Immunology, University of Technology Dresden, Medical Faculty Carl-Gustav Carus, 01307 Dresden, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Rafaels
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Jamora
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Laboratory for Allergic Disease, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama 230-0045, Japan. Electronic address: toshi@lji.org.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000473:pathology
chemical_list: D050799:STAT5 Transcription Factor; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D054799:Phospholipase C beta; C518040:Plcb3 protein, mouse