RRC ID 54352
Author Okuma A, Hoshino K, Ohba T, Fukushi S, Aiba S, Akira S, Ono M, Kaisho T, Muta T.
Title Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease.
Journal Immunity
Abstract Sjögren's syndrome (SS) is an autoimmune disease characterized by exocrinopathy that leads to dry eye and mouth. Although lymphocyte infiltration into exocrine glands and the generation of autoantibodies have been reported in SS, its pathogenic mechanism remains elusive. Here, we show that mice lacking the transcriptional regulator IκB-ζ developed SS-like inflammation characterized by lymphocyte-infiltrated dacryoadenitis and SS-associated autoantibodies. In particular, epithelial cells, but not hematopoietic cells, lacking IκB-ζ were essential for the development of inflammation. IκB-ζ-deficient epithelial cells in the lacrimal glands exhibited enhanced apoptosis even in the absence of lymphocytes. Administration of caspase inhibitors ameliorated the inflammation, indicating the critical role of caspase-mediated apoptosis. Furthermore, epithelial cell-specific STAT3-deficient mice developed SS-like inflammation with impaired IκB-ζ expression in the lacrimal glands. Thus, this study reveals a pathogenic mechanism of SS in which dysfunction of epithelial cells caused by disruption of STAT3-mediated IκB-ζ induction elicits the activation of self-reactive lymphocytes.
Volume 38(3)
Pages 450-60
Published 2013-3-21
DOI 10.1016/j.immuni.2012.11.016
PII S1074-7613(13)00063-0
PMID 23453632
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / immunology Animals Apoptosis / genetics Apoptosis / immunology* Autoimmune Diseases / genetics Autoimmune Diseases / immunology* Autoimmune Diseases / metabolism Epithelial Cells / immunology* Epithelial Cells / metabolism Female Immunohistochemistry In Situ Nick-End Labeling Inflammation / genetics Inflammation / immunology Inflammation / metabolism Lacrimal Apparatus / immunology Lacrimal Apparatus / metabolism Lymphocytes / immunology Lymphocytes / metabolism Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Nuclear Proteins / genetics Nuclear Proteins / immunology STAT3 Transcription Factor / genetics STAT3 Transcription Factor / immunology* STAT3 Transcription Factor / metabolism Signal Transduction / genetics Signal Transduction / immunology Sjogren's Syndrome / genetics Sjogren's Syndrome / immunology* Sjogren's Syndrome / metabolism
IF 22.553
Times Cited 78
DNA material pMY-FLAG-mouse IkB-zeta(D)-IRES-GFP (RDB16741) pcDNA3-FLAG-mouse IkB-zeta(D) (RDB16742)