Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding.
Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor-alpha (TNF-alpha). Adiponectin treatment protects mice from ethanol-induced liver injury. Because adiponectin has anti-inflammatory effects on macrophages, we hypothesized that adiponectin would normalize chronic ethanol-induced sensitization of Kupffer cells to LPS-mediated signals. Serum adiponectin concentrations were decreased by 45% in rats fed an ethanol-containing diet for 4 wk compared with pair-fed rats. Adiponectin dose dependently inhibited LPS-stimulated accumulation of TNF-alpha mRNA and peptide in Kupffer cells from both pair- and ethanol-fed rats. Kupffer cells from ethanol-fed rats were more sensitive to both globular (gAcrp) and full-length adiponectin (flAcrp) than Kupffer cells from pair-fed controls with suppression at 10 ng/ml adiponectin after chronic ethanol feeding. Kupffer cells expressed both adiponectin receptors 1 and 2; chronic ethanol feeding did not change the expression of adiponectin receptor mRNA or protein. gAcrp suppressed LPS-stimulated ERK1/2 and p38 phosphorylation as well as IkappaB degradation at 100-1,000 ng/ml in Kupffer cells from both pair- and ethanol-fed rats. However, only LPS-stimulated ERK1/2 phosphorylation was sensitive to 10 ng/ml gAcrp. gAcrp also normalized LPS-stimulated DNA binding activity of early growth response-1 with greater sensitivity in Kupffer cells from rats fed chronic ethanol. In conclusion, these results demonstrate that Kupffer cells from ethanol-fed rats are more sensitive to the anti-inflammatory effects of both gAcrp and flAcrp. Suppression of LPS-stimulated ERK1/2 signaling by low concentrations of gAcrp was associated with normalization of TNF-alpha production by Kupffer cells after chronic ethanol exposure.
Thakur
Varsha
V
Department of Nutrition, Case Western Reserve University, Rm. 201, 2123 Abington Road, Cleveland, OH 44106-4906, USA.
Pritchard
Michele T
MT
McMullen
Megan R
MR
Nagy
Laura E
LE
D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D052242:Adiponectin; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D000431:Ethanol; D048049:Extracellular Signal-Regulated MAP Kinases