Conclusion: Our novel findings document the key immune regulatory

Conclusion: Our novel findings document the key immune regulatory function of Gsk3β signaling in the pathophysiology of liver IRI, and provide a rationale to target Gsk3β as a refined therapeutic strategy to ameliorate liver IRI. (HEPATOLOGY 2011;) Ischemia and reperfusion injury (IRI) is a common clinical problem associated with liver transplantation, partial hepatic resection, or trauma. Although IRI significantly impacts both acute liver failure/graft rejection, as well as chronic liver dysfunction,1-4 no effective therapy is available to prevent or treat the clinical syndrome. The pathogenesis

of IRI is a two-stage process consisting of the initial cellular damage due to ischemia, followed by reperfusion-initiated inflammation-induced hepatocellular damage. Recently, host innate Toll-like receptor 4 (TLR4) activation by endogenous ligands has been identified as the key trigger in the liver immune response against IR.5-9 As cell surface TLR4 ligation activates Selumetinib price buy Ferrostatin-1 multiple intracellular signaling pathways10, 11 leading to the induction of pro- and anti-inflammatory gene programs, our better appreciation of their regulatory mechanisms should identify novel therapeutic targets to selectively alleviate pro- while sparing or promoting anti-inflammatory immune responses and ultimately ameliorate tissue damage. Recent studies have revealed that glycogen synthase kinase 3β (Gsk3β) may represent such

a target. Indeed, inhibition of Gsk3β in vitro significantly increased interleukin (IL)-10 production while suppressing release of pro-inflammatory cytokines in macrophages stimulated with TLR ligands. TLR activation leads to Gsk3β phosphorylation by the phosphoinositide 3 (PI3) kinase-Akt pathway. The resultant increase of 3′-5′-cyclic adenosine monophosphate

(cAMP) response element-binding (CREB) but decrease of nuclear factor kappa B (NF-κB) activity diminish the expression of pro-inflammatory 4��8C genes, such as IL-12, tumor necrosis factor alpha (TNF-α), and IL-1β, while augmenting the expression of anti-inflammatory IL-10.12In vivo, Gsk3β inhibitors effectively protected mice from endotoxin shock.12 These data suggest the therapeutic potential of Gsk3β inhibition and warrant further confirmation in clinically relevant animal inflammatory disease models. Gsk3, a ubiquitously expressed serine/threonine kinase, was initially found to regulate glycogen synthesis.13, 14 There are two highly homologous Gsk3α and Gsk3β isoforms. Gsk3β, constitutively active (in dephosphorylated form) in resting cells, has a broad range of substrates regulating cell activation, differentiation, and survival. In heart IRI models, Gsk3β inactivation represents the convergence point for multiple cytoprotective signaling pathways.15 Gsk3β regulates the induction of the mitochondrial permeability transition pore (MPTP), a key step in triggering mitochondria-mediated cell death, which constitutes the critical IRI effector pathway.

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