Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes.
OBJECTIVE
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.
Tron
Kyrylo
K
Abteilung Gastroenterologie und Endokrinologie, Uniklinikum, Georg-August-Universität Göttingen, D-37075 Göttingen, Germany.
Samoylenko
Anatoly
A
Musikowski
Gernot
G
Kobe
Fritz
F
Immenschuh
Stephan
S
Schaper
Fred
F
Ramadori
Giuliano
G
Kietzmann
Thomas
T
D000818:Animals; D015152:Blotting, Northern; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D015533:Transcriptional Activation
D015850:Interleukin-6; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat