Prevention of Reg I-induced β-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation

Kei Nakagawa, Shin Takasawa, Koji Nata, Akiyo Yamauchi, Asako Itaya-Hironaka, Hiroyo Ota, Kiyomi Yoshimoto, Sumiyo Sakuramoto-Tsuchida, Tomoko Miyaoka, Maiko Takeda, Michiaki Unno, Hiroshi Okamoto

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Reg (regenerating gene) product, Reg protein, is induced in pancreatic β-cells and acts as autocrine/paracrine growth factor for regeneration via the cell surface Reg receptor. However, high concentrations of Reg I protein induced β-cell apoptosis. In the present study, we found that hepatocyte growth factor (HGF) attenuated the β-cell apoptosis induced by the high concentrations of Reg I protein and that the combined stimulation of interleukin-6 (IL-6) and dexamethasone (Dx) induced the accumulation of HGF mRNA as well as Reg I mRNA in β-cells. The accumulation of the HGF mRNA was caused by the activation of the HGF promoter. Deletion analysis revealed that the region of -. 96 to -. 92 of the HGF gene was responsible for the promoter activation by IL-6. +. Dx. The promoters contain a consensus transcription factor binding sequence for signal transducer and activator of transcription (STAT). Site-directed mutations of STAT-binding motif in the region markedly attenuated the HGF promoter activity. Chromatin immunoprecipitation assay showed that STAT3 is located at the active HGF promoter in response to IL-6. +. Dx stimulation. These results strongly suggest that the combined stimulation of IL-6 and glucocorticoids induces the activation of both Reg and HGF genes and that the anti-apoptotic effects of HGF against the Reg I-induced apoptosis may help β-cell regeneration by Reg I protein.

Original languageEnglish
Pages (from-to)2988-2995
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number12
DOIs
Publication statusPublished - 2013 Dec

Keywords

  • Glucocorticoids
  • HGF gene
  • IL-6
  • Pancreatic β cell
  • Reg protein
  • Transcriptional control

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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