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

详细信息    查看全文

• 作者：Nicolas Coant¹ ; ² ; ^&dagger ; ; Marika Simon-Rudler¹ ; ^&dagger ; ; Thierry Gustot¹ ; ³ ; ^&dagger ; ; ^{tgustot@ulb.ac.be} ; Magali Fasseu¹ ; Sonia Gandoura¹ ; Ké ; vin Ragot⁴ ; Waë ; l Abdel-Razek⁵ ; Dominique Thabut¹ ; Philippe Letté ; ron¹ ; ² ; Eric Ogier-Denis¹ ; ² ; Romy Ouziel³ ; Jacques Deviè ; re³ ; Gé ; rard Lizard⁴ ; Zé ; ra Tellier⁶ ; Didier Lebrec¹ ; ² ; ⁵ ; Richard Moreau¹ ; ² ; ⁵
• 关键词：Cirrhosis ; Alcohol ; Innate immunity ; Lipopolysaccharides ; AKT ; Glycogen synthase kinase 3
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：October, 2011
• 年：2011
• 卷：55
• 期：4
• 页码：784-793
• 全文大小：1K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

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¦Â (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3¦Â (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¦Â phosphorylation was assessed using Western blotting.

Results

In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins TNF-¦Á and IL-12p40 was significantly decreased while that of IL-10 was increased. LPS-induced, AKT-mediated phosphorylation of GSK3¦Â 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¦Â phosphorylation resulting in unrestricted ¡®pro-inflammatory?activity of the enzyme.