Article

The Anti-Inflammatory Effects of Adiponectin Are Mediated via a Heme Oxygenase-1-Dependent Pathway in Rat Kupffer Cells

Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Hepatology (Impact Factor: 11.06). 04/2010; 51(4):1420-9. DOI: 10.1002/hep.23427
Source: PubMed

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. Conclusion: 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.

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    • "However, pharmacological induction of HO-1 prevents ethanol-induced inflammation in the intestine [8], as well as oxidative damage and apoptosis in cultured hepatocytes [9] [10]. Further, HO-1-mediated pathways can be activated in Kupffer cells after chronic ethanol feeding to suppress TLR4-dependent signalling in primary cultures of Kupffer cells, as well as in an in vivo mouse model of LPS challenge [5] [11]. "

    Full-text · Dataset · Nov 2014
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    • "However, pharmacological induction of HO-1 prevents ethanol-induced inflammation in the intestine [8], as well as oxidative damage and apoptosis in cultured hepatocytes [9] [10]. Further, HO-1-mediated pathways can be activated in Kupffer cells after chronic ethanol feeding to suppress TLR4-dependent signalling in primary cultures of Kupffer cells, as well as in an in vivo mouse model of LPS challenge [5] [11]. "
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    Full-text · Article · Nov 2014 · Journal of Hepatology
    • "Systemic provision of pharmaceutical agents makes it difficult to determine the precise site of therapeutic action. Making use of primary cultures, induction of HO-1 or the provision of CORM-A1 ameliorated the impact of ethanol in both Kupffer cells [5] [11] and hepatocytes (Fig. 4), suggesting that these two cell types are key targets for the protective effects of HO-1/CO. However, it is also possible that additional cell types/organs contribute to the protective effects of HO-1/CO in vivo. "
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    ABSTRACT: Background & aims: Alcoholic liver disease is associated with inflammation and cell death. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-apoptotic and anti-inflammatory properties. Here we tested the hypothesis that induction of HO-1 or treatment with a carbon monoxide releasing molecule (CORM) during chronic ethanol exposure protects and/or reverses ethanol-induced liver injury. Methods: Female C57BL/6J mice were allowed free access to a complete liquid diet containing ethanol or to pair-fed control diets for 25days. Mice were treated with cobalt protoporphyrin (CoPP) to induce HO-1 expression during ethanol feeding or once liver injury had been established. Mice were also treated with CORM-A1, a CO-releasing molecule (CORM), after ethanol-induced liver injury was established. The impact of HO-1 induction on ethanol-induced cell death was investigated in primary cultures of hepatocytes. Results: Induction of HO-1 during or after ethanol feeding, as well as treatment with CORM-A1, ameliorated ethanol-induced increases in AST and expression of mRNAs for inflammatory cytokines. Treatment with CoPP or CORM-A1 also reduced hepatocyte cell death, indicated by decreased accumulation of CK18 cleavage products and reduced RIP3 expression in hepatocytes. Exposure of primary hepatocyte cultures to ethanol increased their sensitivity to TNFα-induced cell death; this response was attenuated by necrostatin-1, an inhibitor of necroptosis, but not by caspase inhibitors. Induction of HO-1 with CoPP or CORM-3 treatment normalized the sensitivity of hepatocytes to TNFα-induced cell death after ethanol exposure. Conclusions: Therapeutic strategies to increase HO-1 and/or modulate CO availability ameliorated chronic ethanol-induced liver injury in mice, at least in part by decreasing hepatocellular death.
    No preview · Article · Jun 2014 · Journal of Hepatology
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