Thakur Varsha, Pritchard Michele T, McMullen Megan R, Nagy Laura E
Department of Nutrition, Case Western Reserve University, Rm. 201, 2123 Abington Road, Cleveland, OH 44106-4906, USA.
Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G998-1007. doi: 10.1152/ajpgi.00553.2005. Epub 2006 Jan 12.
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.
长期喂养乙醇会使库普弗细胞对脂多糖（LPS）的激活更加敏感，从而导致肿瘤坏死因子-α（TNF-α）的产生增加。脂联素治疗可保护小鼠免受乙醇诱导的肝损伤。由于脂联素对巨噬细胞具有抗炎作用，我们推测脂联素会使长期乙醇诱导的库普弗细胞对LPS介导信号的敏感性恢复正常。与配对喂养的大鼠相比，喂食含乙醇饮食4周的大鼠血清脂联素浓度降低了45%。脂联素剂量依赖性地抑制了配对喂养和乙醇喂养大鼠的库普弗细胞中LPS刺激的TNF-α mRNA和肽的积累。与配对喂养的对照大鼠的库普弗细胞相比，乙醇喂养大鼠的库普弗细胞对球状（gAcrp）和全长脂联素（flAcrp）都更敏感，长期乙醇喂养后，在10 ng/ml脂联素时受到抑制。库普弗细胞表达脂联素受体1和2；长期乙醇喂养并未改变脂联素受体mRNA或蛋白的表达。gAcrp在100 - 1000 ng/ml时抑制了配对喂养和乙醇喂养大鼠的库普弗细胞中LPS刺激的ERK1/2和p38磷酸化以及IκB降解。然而，只有LPS刺激的ERK1/2磷酸化对10 ng/ml gAcrp敏感。gAcrp还使长期乙醇喂养大鼠的库普弗细胞中LPS刺激的早期生长反应-1的DNA结合活性恢复正常，且敏感性更高。总之，这些结果表明，乙醇喂养大鼠的库普弗细胞对gAcrp和flAcrp的抗炎作用更敏感。低浓度gAcrp对LPS刺激的ERK1/2信号的抑制与长期乙醇暴露后库普弗细胞TNF-α产生的恢复正常有关。
