GSK3β-Dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury

Dae Won Park, Shaoning Jiang, Yanping Liu, Gene P. Siegal, Ken Inoki, Edward Abraham, Jaroslaw W. Zmijewski

Research output: Contribution to journalArticle

40 Citations (Scopus)

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, despite 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 (ALI). Since 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 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 (6-bromoindirubin-3′-oxime), 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 phosphorylation and inactivation AMPK by GSK3β. Inhibition of GSK3β activity delayed IκBα degradation and diminished expression of the proinflammatory TNF-α in LPS-stimulated neutrophils and macrophages. In vivo, inhibition of GSK3β decreased the severity of LPS-induced lung injury as assessed by development of pulmonary edema, production of TNF-α and MIP-2, and release of the alarmins HMGB1 and histone 3 in the lungs. These results show that inhibition of AMPK by GSK3β plays an important contributory role in enhancing LPS-induced inflammatory responses, including worsening the severity of ALI.

Original languageEnglish
Pages (from-to)L735-L745
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume307
Issue number10
DOIs
Publication statusPublished - 2014 Jan 1

Keywords

  • Acute lung injury
  • AMPK
  • GSK3β
  • IKK
  • Inflammation

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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