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

par Coant, Nicolas;Simon-Rudler, Marika;Gustot, Thierry ;Fasseu, Magali;Gandoura, Sonia;Ragot, Kévin;Abdel-Razek, Waël;Thabut, Dominique;Lettéron, Philippe;Ogier-Denis, Eric;Ouziel, Romy ;Devière, Jacques ;Lizard, Gérard;Tellier, Zéra;Lebrec, Didier;Moreau, R.
Référence Journal of hepatology, 55, 4, page (784-793)
Publication Publié, 2011-10

Article révisé par les pairs

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Résumé :

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 GSK3β (one of two GSK3 isoforms) on Ser9. Phosphorylation of GSK3β (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.