Prevention of Reg I-induced ß-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation.
Biochim Biophys Acta
; 1833(12): 2988-2995, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-23954444
ABSTRACT
Reg (regenerating gene) product, Reg protein, is induced in pancreatic ß-cells and acts as autocrine/paracrine growth factor for regeneration via the cell surface Reg receptor. However, high concentrations of Reg I protein induced ß-cell apoptosis. In the present study, we found that hepatocyte growth factor (HGF) attenuated the ß-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 ß-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 ß-cell regeneration by Reg I protein.
Palavras-chave
3-aminobenzamide; 3AB; 4[-3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate; ChIP; Chromatin immunoprecipitation; Dx; FCS; GAPDH; GATA; Glucocorticoids; HGF; HGF gene; HSF-2; IL-6; NA; NOD mouse; Nrf-2; PARP; Pancreatic ß cell; RT-PCR; Reg; Reg protein; STAT; Transcriptional control; WST-1; dexamethasone; fetal calf serum; glyceraldehyde-3-phosphate dehydrogenase; heart shock factor 2; hepatocyte growth factor; interleukin-6; nicotinamide; non-obese diabetic mouse; nuclear respiratory factor 2; poly(ADP-ribose) polymerase; regenerating gene; reverse transcription polymerase chain reaction; signal transducer and activator of transcription; transcription factor
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dexametasona
/
Regulação da Expressão Gênica
/
Interleucina-6
/
Fator de Crescimento de Hepatócito
/
Apoptose
/
Células Secretoras de Insulina
/
Litostatina
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Japão