title: Synergistic activations of REG I α and REG I β promoters by IL-6 and Glucocorticoids through JAK/STAT pathway in human pancreatic β cells.
abstract: Reg (Regenerating gene) gene was originally isolated from rat regenerating islets and its encoding protein was revealed as an autocrine/paracrine growth factor for β cells. Rat Reg gene is activated in inflammatory conditions for β cell regeneration. In human, although five functional REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) were isolated, their expressions in β cells under inflammatory conditions remained unclear. In this study, we found that combined addition of IL-6 and dexamethasone (Dx) induced REG Iα and REG Iβ expression in human 1.1B4 β cells. Promoter assay revealed that a signal transducer and activator of transcription- (STAT-) binding site in each promoter of REG Iα (TGCCGGGAA) and REG Iβ (TGCCAGGAA) was essential for the IL-6+Dx-induced promoter activation. A Janus kinase 2 (JAK2) inhibitor significantly inhibited the IL-6+Dx-induced REG Iα and REG Iβ transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed that IL-6+Dx stimulation increased STAT3 binding to the REG Iα promoter. Furthermore, small interfering RNA-mediated targeting of STAT3 blocked the IL-6+Dx-induced expression of REG Iα and REG Iβ. These results indicate that the expression of REG Iα and REG Iβ should be upregulated in human β cells under inflammatory conditions through the JAK/STAT pathway.
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Itaya-Hironaka
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Sumiyo
authors.initials: S
authors.lastname: Sakuramoto-Tsuchida
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Yoshimoto
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyaoka
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsujinaka
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Chikatsugu
authors.initials: C
authors.lastname: Tsuchida
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Ota
authors.affiliation: Department of Biochemistry, Nara Medical University, Kashihara 634-8521, Japan.
authors.forename: Shin
authors.identifier: 0000-0002-4066-0199
authors.initials: S
authors.lastname: Takasawa
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology; D053613:Janus Kinase 1 / Q000378:metabolism*; D051847:Lithostathine / Q000235:genetics*; D000073718:Pancreatitis-Associated Proteins; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D015850:Interleukin-6; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; C497617:REG1A protein, human; C497618:REG1B protein, human; C000612141:REG3A protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1