GSK3β-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages, and enhances severity of acute lung injury.

GSK3β-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages, and enhances severity of acute lung injury.
Am J Physiol Lung Cell Mol Physiol. 2014 Sep 19;
Authors: Park DW, Jiang S, Liu Y, Siegal GP, Inoki K, Abraham E, Zmijewski JW
Abstract
Although AMP-activated protein kinase (AMPK) is involved in regulating carbohydrate and lipid metabolism, activated AMPK also plays an anti-inflammatory role in many cell populations. However, in spite of the ability of AMPK activation to diminish the severity of inflammatory responses, previous studies have found that AMPK activity is diminished in LPS-treated neutrophils and also in lungs of mice with LPS-induced acute lung injury. As GSK3β participates in regulating AMPK activity, we examined potential roles for GSK3β in modulating LPS-induced activation of neutrophils and macrophages, and in influencing severity of acute lung injury (ALI). We found that GSK3β-dependent phosphorylation of T479-AMPK was associated with pT172 dephosphorylation and inactivation of AMPK following TLR4 engagement. GSK3β inhibitors BIO, SB216763 or siRNA knockdown of GSK3β, but not the PI3K/AKT inhibitor LY294002, prevented Thr172-AMPK dephosphorylation. Exposure to LPS resulted in rapid binding between IKKβ and AMPKα, and phosphorylation of S485-AMPK by IKKβ. These results suggest that IKKβ-dependent phosphorylation of S485-AMPK was an essential step in subsequent phosphorylati...

Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - September 19, 2014 Category: Cytology Authors: Park DW, Jiang S, Liu Y, Siegal GP, Inoki K, Abraham E, Zmijewski JW Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research