Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2006-05, Vol.290 (5), p.G998-G1007
• Main Authors: Thakur, Varsha, Pritchard, Michele T, McMullen, Megan R, Nagy, Laura E
• Format: Article
• Language: English
• Subjects: Adiponectin - metabolism; Animals; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Early Growth Response Protein 1 - metabolism; Ethanol - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; I-kappa B Proteins - metabolism; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Lipopolysaccharides - pharmacology; Male; Phosphorylation; Rats; Rats, Wistar; Receptors, Adiponectin; Receptors, Cell Surface - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00553.2005

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.