title: Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure.
abstract: Alcoholic liver disease is mediated via activation of TLR4 signaling; MyD88-dependent and -independent signals are important contributors to injury in mouse models. Adiponectin, an anti-inflammatory adipokine, suppresses TLR4/MyD88-dependent responses via induction of heme oxygenase-1 (HO-1). Here we investigated the interactions between chronic ethanol, adiponectin, and HO-1 in regulation of TLR4/MyD88-independent signaling in macrophages and an in vivo mouse model. After chronic ethanol feeding, LPS-stimulated expression of IFN-β and CXCL10 mRNA was increased in primary cultures of Kupffer cells compared with pair-fed control mice. Treatment of Kupffer cells with globular adiponectin (gAcrp) normalized this response. LPS-stimulated IFN-β/CXCL10 mRNA and CXCL10 protein was also reduced in RAW 264.7 macrophages treated with gAcrp or full-length adiponectin. gAcrp and full-length adiponectin acted via adiponectin receptors 1 and 2, respectively. gAcrp decreased TLR4 expression in both Kupffer cells and RAW 264.7 macrophages. Small interfering RNA knockdown of HO-1 or inhibition of HO-1 activity with zinc protoporphyrin blocked these effects of gAcrp. C57BL/6 mice were exposed to chronic ethanol feeding, with or without treatment with cobalt protoporphyrin, to induce HO-1. After chronic ethanol feeding, mice were sensitized to in vivo challenge with LPS, expressing increased IFN-β/CXCL10 mRNA and CXCL10 protein in liver compared with control mice. Pretreatment with cobalt protoporphyrin 24 h before LPS challenge normalized this effect of ethanol. Adiponectin and induction of HO-1 potently suppressed TLR4-dependent/MyD88-independent cytokine expression in primary Kupffer cells from rats and in mouse liver after chronic ethanol exposure. These data suggest that induction of HO-1 may be a useful therapeutic strategy in alcoholic liver disease.
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Palash
authors.initials: P
authors.lastname: Mandal
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.forename: Brian T
authors.initials: BT
authors.lastname: Pratt
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D002491:Central Nervous System Agents / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D002491:Central Nervous System Agents; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D000431:Ethanol; D051547:Heme Oxygenase-1