Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor (TNF ). Adiponectin treatment protects mice from ethanol-induced liver injury. Since 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 wks compared to pair-fed rats. Adiponectin dose-dependently inhibited LPS-stimulated accumulation of TNF 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 (flAcrp) adiponectin than Kupffer cells from pair-fed controls with suppression at 10 ng/ml Acrp after chronic ethanol feeding. Kupffer cells expressed both adiponectin R1 and R2 receptors; chronic ethanol feeding did not change expression of adiponectin receptor mRNA or protein. gAcrp suppressed LPS-stimulated ERK1/2 and p38 phosphorylation, as well as IB degradation, at 100-1000 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 Egr-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 production by Kupffer cells after chronic ethanol exposure.