BACKGROUND/AIMS: Heme oxygenase-1 (HO-1) can be induced by various stimuli, one of which is interleukin-6 (IL-6). Therefore, the aim of this study was to elucidate the molecular mechanisms responsible for IL-6-dependent HO-1 induction in the liver. METHODS: The IL-6-dependent HO-1 regulation in rat primary hepatocytes and HepG2 hepatoma cells was studied by Northern and Western blot analyses, HO-1 promoter reporter gene assays and EMSA. RESULTS: The HO-1 expression was transcriptionally induced by IL-6 in a time- and dose-dependent manner. Activation of signal transducers and activators of transcription (STAT) factors by the IL-6 receptor was crucial for HO-1 induction. By contrast, negative regulation of HO-1 expression appeared to be mediated through the SH2-domain-containing tyrosine phosphatase-2 (SHP2)/ suppressors of cytokine signaling-3 (SOCS3) binding site within the gp130 IL-6 receptor subunit. Among the three putative STAT binding elements (SBE) in the HO-1 promoter, only the distal one was functional and when deleted, the remaining Luc induction was completely obliterated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. CONCLUSIONS: The HO-1 SBE3 mediates HO-1 gene induction by IL-6 mainly via activation of the Jak/STAT pathway.
BACKGROUND/AIMS: Heme oxygenase-1 (HO-1) can be induced by various stimuli, one of which is interleukin-6 (IL-6). Therefore, the aim of this study was to elucidate the molecular mechanisms responsible for IL-6-dependent HO-1 induction in the liver. METHODS: The IL-6-dependent HO-1 regulation in rat primary hepatocytes and HepG2 hepatoma cells was studied by Northern and Western blot analyses, HO-1 promoter reporter gene assays and EMSA. RESULTS: The HO-1 expression was transcriptionally induced by IL-6 in a time- and dose-dependent manner. Activation of signal transducers and activators of transcription (STAT) factors by the IL-6 receptor was crucial for HO-1 induction. By contrast, negative regulation of HO-1 expression appeared to be mediated through the SH2-domain-containing tyrosine phosphatase-2 (SHP2)/ suppressors of cytokine signaling-3 (SOCS3) binding site within the gp130 IL-6 receptor subunit. Among the three putative STAT binding elements (SBE) in the HO-1 promoter, only the distal one was functional and when deleted, the remaining Luc induction was completely obliterated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. CONCLUSIONS: The HO-1 SBE3 mediates HO-1 gene induction by IL-6 mainly via activation of the Jak/STAT pathway.
Authors: Claire Mayeur; Lisa K Lohmeyer; Patricio Leyton; Sonya M Kao; Alexandra E Pappas; Starsha A Kolodziej; Ester Spagnolli; Binglan Yu; Rita L Galdos; Paul B Yu; Randall T Peterson; Donald B Bloch; Kenneth D Bloch; Andrea U Steinbicker Journal: Blood Date: 2014-02-05 Impact factor: 22.113
Authors: M J Tracz; J P Juncos; A J Croatt; A W Ackerman; J P Grande; K L Knutson; G C Kane; A Terzic; M D Griffin; K A Nath Journal: Kidney Int Date: 2007-08-29 Impact factor: 10.612
Authors: Zhaowen Zhu; Anne T Wilson; M Meleah Mathahs; Feng Wen; Kyle E Brown; Bruce A Luxon; Warren N Schmidt Journal: Hepatology Date: 2008-11 Impact factor: 17.425
Authors: Apriliana E R Kartikasari; Frank A D T G Wagener; Akihiro Yachie; Erwin T G Wiegerinck; Erwin H J M Kemna; Dorine W Swinkels; Dorine W Winkels Journal: J Cell Mol Med Date: 2009-09-04 Impact factor: 5.310