title: Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Iα, a New Autoantigen in Sjögren's Syndrome Patients, in Salivary Duct Epithelial Cells.
abstract: The regenerating gene, Reg, was originally isolated from a rat regenerating islet complementary DNA (cDNA) library, and its human homologue was named REG Iα. Recently, we reported that REG Iα messenger RNA (mRNA), as well as its product, was overexpressed in ductal epithelial cells in the salivary glands of Sjögren's syndrome patients. Furthermore, autoantibodies against REG Iα were found in the sera of Sjögren's syndrome patients, and the patients who were positive for the anti-REG Iα antibody showed significantly lower saliva secretion than antibody-negative patients. We found the mechanism of REG Iα induction in salivary ductal epithelial cells. Reporter plasmid containing REG Iα promoter (-1190/+26) upstream of a luciferase gene was introduced into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with several cytokines (interleukin (IL)-6, IL-8, etc.), upregulated in Sjögren's syndrome salivary ducts, and the transcriptional activity was measured. IL-6 stimulation significantly enhanced the REG Iα promoter activity in both cells. Deletion analysis revealed that the -141∼-117 region of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transducer and activator of transcription (STAT) binding. The introduction of small interfering RNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results indicated that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the REG Iα promoter in salivary ductal cells. This dependence of REG Iα induction upon IL-6/STAT in salivary duct epithelial cells may play an important role in the pathogenesis/progression of Sjögren's syndrome.
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.|The Center for Rheumatic Diseases, Nara Medical University Hospital, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: The Center for Rheumatic Diseases, Nara Medical University Hospital, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Itaya-Hironaka
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.|The Center for Rheumatic Diseases, Nara Medical University Hospital, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyaoka
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.|Department of General Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Yoshimoto
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.
authors.forename: Sumiyo
authors.initials: S
authors.lastname: Sakuramoto-Tsuchida
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.|Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan.|Department of Ophthalmology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsujinaka
authors.affiliation: The Center for Rheumatic Diseases, Nara Medical University Hospital, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan. shintksw@naramed-u.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Takasawa
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051847:Lithostathine / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D050791:STAT Transcription Factors / Q000378:metabolism*; D018987:Salivary Ducts / Q000473:pathology*; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015850:Interleukin-6; D051847:Lithostathine; C497617:REG1A protein, human; D050791:STAT Transcription Factors
keywords: Autoantibody; Interleukin-6; Janus kinase (JAK); Regenerating gene (Reg); Signal transducer and activator of transcription (STAT); Sjögren’s syndrome