title: Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease.
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.
authors: Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors: Atsushi
authors: A
authors: Okuma
authors: Katsuaki
authors: K
authors: Hoshino
authors: Tomoyuki
authors: T
authors: Ohba
authors: Sawako
authors: S
authors: Fukushi
authors: Setsuya
authors: S
authors: Aiba
authors: Shizuo
authors: S
authors: Akira
authors: Masao
authors: M
authors: Ono
authors: Tsuneyasu
authors: T
authors: Kaisho
authors: Tatsushi
authors: T
authors: Muta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007765:Lacrimal Apparatus / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse