IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway

AIMS: The present study was conducted to explore the effect of interleukin-33 (IL-33) on glycogen synthase kinase-3β (GSK-3β) activation involving Tau phosphorylation, a critical causative factor for Alzheimer's disease (AD). MAIN METHODS: Experiments were performed using PC-12 cells. Target proteins were knocked-down by transfecting with the siRNA for each protein. The kinase activities were assessed by monitoring phosphorylation of Thr308 and Ser473 for Akt and phosphorylation of Ser9 and Tyr216 for GSK-3β in the Western blotting. KEY FINDINGS: Exogenously applied IL-33 activated Akt and inactivated GSK-3β. IL-33-induced Akt activation and GSK-3β inactivation were significantly inhibited by knocking-down myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), receptor-interacting protein (RIP), or phosphatidylinositol 3 kinase (PI3K). IL-33 neutralized amyloid β(1-42) (Aβ(1-42))-induced Akt inactivation and GSK-3β activation. SIGNIFICANCE: The results of the present study show that IL-33 inactivates GSK-3β through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway and inhibits Aβ(1-42)-induced GSK-3β activation. This suggests that IL-33 could restrain GSK-3β-mediated Tau phosphorylation in AD.