1. Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes.
- Author
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Tron K, Samoylenko A, Musikowski G, Kobe F, Immenschuh S, Schaper F, Ramadori G, and Kietzmann T
- Subjects
- Animals, Blotting, Northern, Cell Culture Techniques, Dose-Response Relationship, Drug, Hepatocytes drug effects, Kinetics, Male, Plasmids, RNA, Messenger genetics, Rats, Rats, Wistar, Signal Transduction immunology, Transcriptional Activation, Gene Expression Regulation, Enzymologic drug effects, Heme Oxygenase (Decyclizing) genetics, Hepatocytes enzymology, Interleukin-6 pharmacology, Signal Transduction drug effects
- Abstract
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.
- Published
- 2006
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