Glycogen synthase kinase 3 involvement in the excessive proinflammatory response to LPS in XXXX with decompensated @entity82 .

@entity1 @entity13557 @entity82 @entity310 @entity584 @entity25650 @entity2939 @entity688 @entity9459
BACKGROUND _ AIMS: In decompensated @entity82 , the early innate immune response to the @entity2939 ( @entity2939 ) agonist, lipopolysaccharides (LPS), is characterized by a hyper-production of pro-inflammatory cytokines and hypo-production of the anti-inflammatory cytokine @entity688 . 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, @entity2939 dampens its own pro-inflammatory response by inducing early (within minutes) @entity584 -mediated phosphorylation of @entity9459 (one of two GSK3 isoforms) on Ser9. Phosphorylation of @entity9459 (Ser9) inhibits its activity, decreases pro-inflammatory cytokines, and increases @entity688 . Thus, we investigated the role of GSK3 in LPS-induced cytokine production by peripheral blood mononuclear cells (PBMCs) or monocytes from @entity1 with advanced @entity82 and normal subjects. METHODS: Cells were pre-incubated with or without GSK3 inhibitor ( @entity25650 or @entity13557 ) for 1h and then stimulated with LPS. Cytokine production was assessed at mRNA and secreted proteins levels, by real-time RT-PCR at 1h and ELISA at 20 h, respectively. @entity9459 phosphorylation was assessed using Western blotting. RESULTS: In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory proteins @entity310 and IL-12p40 was significantly decreased while that of @entity688 was increased. LPS-induced, @entity584 -mediated phosphorylation of @entity9459 on Ser9 found in normal monocytes, was abolished in cirrhotic cells. CONCLUSIONS: GSK3 is involved in the early @entity2939 -mediated pro-inflammatory response in @entity1 with decompensated @entity82 . This was associated with a defect in @entity584 -mediated @entity9459 phosphorylation resulting in unrestricted 'pro-inflammatory' activity of the enzyme.
