title: The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells.
abstract: Altered expression and activity of immunomodulatory cytokines plays a major role in the pathogenesis of alcoholic liver disease. Chronic ethanol feeding increases the sensitivity of Kupffer cells, the resident hepatic macrophage, to lipopolysaccharide (LPS), leading to increased tumor necrosis factor alpha (TNF-alpha) expression. This sensitization is normalized by treatment of primary cultures of Kupffer cells with adiponectin, an anti-inflammatory adipokine. Here we tested the hypothesis that adiponectin-mediated suppression of LPS signaling in Kupffer cells is mediated via an interleukin-10 (IL-10)/heme oxygenase-1 (HO-1) pathway after chronic ethanol feeding. Knockdown of IL-10 expression in primary cultures of Kupffer cells with small interfering RNA (siRNA) prevented the inhibitory effect of globular adiponectin (gAcrp) on LPS-stimulated TNF-alpha expression. gAcrp increased IL-10 mRNA and protein expression, as well as expression of the IL-10 inducible gene, HO-1; expression was higher in Kupffer cells from ethanol-fed rats compared with pair-fed controls. Although IL-10 receptor surface expression on Kupffer cells was not affected by ethanol feeding, IL-10-mediated phosphorylation of STAT3 and expression of HO-1 was higher in Kupffer cells after ethanol feeding. Inhibition of HO-1 activity, either by treatment with the HO-1 inhibitor zinc protoporphyrin or by siRNA knockdown of HO-1, prevented the inhibitory effect of gAcrp on LPS-stimulated TNF-alpha expression in Kupffer cells. LPS-stimulated TNF-alpha expression in liver was increased in mice after chronic ethanol exposure. When mice were treated with cobalt protoporphyrin to induce HO-1 expression, ethanol-induced sensitivity to LPS was ameliorated.
  
  
  CONCLUSIONS
  gAcrp prevents LPS-stimulated TNF-alpha expression in Kupffer cells through the activation of the IL-10/STAT3/HO-1 pathway. Kupffer cells from ethanol-fed rats are highly sensitive to the anti-inflammatory effects of gAcrp; this sensitivity is associated with both increased expression and sensitivity to IL-10.
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
authors.forename: Palash
authors.initials: P
authors.lastname: Mandal
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.forename: Brian T
authors.initials: BT
authors.lastname: Pratt
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000431:Ethanol / Q000633:toxicity; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology; D007728:Kupffer Cells / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D052242:Adiponectin; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000431:Ethanol; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat