TY - JOUR
T1 - Prevention of Reg I-induced β-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation
AU - Nakagawa, Kei
AU - Takasawa, Shin
AU - Nata, Koji
AU - Yamauchi, Akiyo
AU - Itaya-Hironaka, Asako
AU - Ota, Hiroyo
AU - Yoshimoto, Kiyomi
AU - Sakuramoto-Tsuchida, Sumiyo
AU - Miyaoka, Tomoko
AU - Takeda, Maiko
AU - Unno, Michiaki
AU - Okamoto, Hiroshi
N1 - Funding Information:
The authors are grateful to Mr. Yuya Shichinohe for technical assistance and Mr. Brent Bell for critical reading of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan , and Japan Science and Technology Agency and is in partial fulfillment by K. Nakagawa of the degree of Doctor of Medical Science at Tohoku University.
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Glucocorticoids
KW - HGF gene
KW - IL-6
KW - Pancreatic β cell
KW - Reg protein
KW - Transcriptional control
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U2 - 10.1016/j.bbamcr.2013.08.004
DO - 10.1016/j.bbamcr.2013.08.004
M3 - Article
C2 - 23954444
AN - SCOPUS:84883362008
VL - 1833
SP - 2988
EP - 2995
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
SN - 0167-4889
IS - 12
ER -