Glycogen synthase kinase 3 involvement in the excessive proinflammatory response to LPS in patients with decompensated cirrhosis

被引:52
作者
Coant, Nicolas [2 ,3 ,4 ]
Simon-Rudler, Marika [2 ,3 ]
Gustot, Thierry [1 ,2 ,3 ]
Fasseu, Magali [2 ,3 ]
Gandoura, Sonia [2 ,3 ]
Ragot, Kevin [5 ]
Abdel-Razek, Wael [6 ]
Thabut, Dominique [2 ,3 ]
Letteron, Philippe [2 ,3 ,4 ]
Ogier-Denis, Eric [2 ,3 ,4 ]
Ouziel, Romy [1 ]
Deviere, Jacques [1 ]
Lizard, Gerard [5 ]
Tellier, Zera [7 ]
Lebrec, Didier [2 ,3 ,4 ,6 ]
Moreau, Richard [2 ,3 ,4 ,6 ]
机构
[1] Univ Libre Bruxelles, Erasme Hosp, Dept Gastroenterol & Hepatopancreatol, Brussels, Belgium
[2] Ctr Rech Biomed Bichat Beaujon CRB3, INSERM, U773, Paris, France
[3] Ctr Rech Biomed Bichat Beaujon CRB3, INSERM, U773, Clichy, France
[4] Univ Paris 07, F-75018 Paris, France
[5] Fac Sci Gabriel, INSERM, U866, Dijon, France
[6] Hop Beaujon, AP HP, Serv Hepatol, Clichy, France
[7] Lab Francais Fractionnement & Biotechnol, Courtaboeuf, France
关键词
Cirrhosis; Alcohol; Innate immunity; Lipopolysaccharides; AKT; Glycogen synthase kinase 3; NECROSIS-FACTOR-ALPHA; ALCOHOLIC LIVER-DISEASE; ACUTE ETHANOL TREATMENT; FLOW-CYTOMETRIC ASSAYS; CYTOKINE PRODUCTION; DENDRITIC CELLS; TNF EXPRESSION; IRAK-M; PROTEIN; LIPOPOLYSACCHARIDE;
D O I
10.1016/j.jhep.2010.12.039
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: In decompensated cirrhosis, the early innate immune response to the Toll-like receptor 4 (TLR4) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine IL-10. In LPS-stimulated non-cirrhotic immune cells, the constitutively active glycogen synthase kinase (GSK) 3 favors pro- vs. anti-inflammatory cytokines, by acting on gene induction. However, in these cells, TLR4 dampens its own pro-inflammatory response by inducing early (within minutes) AKT-mediated phosphorylation of GSK3 beta (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3 beta (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases IL-10. Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from patients with advanced cirrhosis and normal subjects. Methods: Cells were pre-incubated with or without GSK3 inhibitor (SB216763 or lithium chloride) for 1 h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1 h and ELISA at 20 h, respectively. GSK3 beta phosphorylation was assessed using Western blotting. Results: In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-alpha and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3b on Ser9 found in normal monocytes, was abolished in cirrhotic cells. Conclusions: GSK3 is involved in the early TLR4-mediated pro-inflammatory response in patients with decompensated cirrhosis. This was associated with a defect in AKT-mediated GSK3 beta phosphorylation resulting in unrestricted 'pro-inflammatory' activity of the enzyme. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:784 / 793
页数:10
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