title: Reciprocal regulation of IL-6 and IL-10 balance by HGF via recruitment of heme oxygenase-1 in macrophages for attenuation of liver injury in a mouse model of endotoxemia.
abstract: Acute liver injury is a clinical hallmark of endotoxemia regarding the features of septic organ failure. In this process, interleukin (IL)-6 and IL-10 are key contributors for eliciting pro- and anti-inflammatory responses, respectively. In contrast, heme oxygenase-1 (HO-1) provides a defense mechanism against endotoxemia by controlling the IL-6/IL-10 balance, but how higher levels of HO-1 are sustained under pathological conditions remains unknown. Using a mouse model of endotoxemia, we provide evidence to show that hepatocyte growth factor (HGF) enhances HO-1 expression in macrophages, thereby up-regulating IL-10 and down-regulating IL-6 productions. Lipopolysaccharide (LPS)-treated mice manifested acute liver injury similar to that observed in septic patients, while administration of recombinant HGF enhanced expression of HO-1 by hepatic macrophages in vivo. As a result, HGF blocked the onset of hepatic injuries in LPS-treated mice. More importantly, when an HO-1 inhibitor (Sn-PP) was administered with HGF into LPS-treated mice, the protective effects of HGF against hepatic injury were attenuated. Furthermore, Sn-PP partially restored the HGF-mediated decrease in plasma IL-6 levels, while it inhibited the HGF-stimulated increase in plasma IL-10 levels. In the culture of macrophages (Raw264.7), HGF enhanced the LPS-mediated HO-1 induction, and this effect was abolished by cycloheximide, but not by actinomycin-D, thus suggesting that a post-transcriptional pathway is involved in HGF-mediated up-regulation of HO-1. Based on the current data, we conclude that up-regulation of HO-1 plays an important role in HGF-mediated hepatoprotection during endotoxemia, by favoring production of IL-10 over IL-6.
authors: Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan.
authors: Miyuki
authors: M
authors: Kamimoto
authors: Shinya
authors: S
authors: Mizuno
authors: Toshikazu
authors: T
authors: Nakamura
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016753:Interleukin-10; D017228:Hepatocyte Growth Factor; D051547:Heme Oxygenase-1