| First Author | Park DW | Year | 2014 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 307 |
| Issue | 10 | Pages | L735-45 |
| PubMed ID | 25239914 | Mgi Jnum | J:222193 |
| Mgi Id | MGI:5644110 | Doi | 10.1152/ajplung.00165.2014 |
| Citation | Park DW, et al. (2014) GSK3beta-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury. Am J Physiol Lung Cell Mol Physiol 307(10):L735-45 |
| abstractText | 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 GSK3beta participates in regulating AMPK activity, we examined potential roles for GSK3beta in modulating LPS-induced activation of neutrophils and macrophages and in influencing severity of ALI. We found that GSK3beta-dependent phosphorylation of T479-AMPK was associated with pT172 dephosphorylation and inactivation of AMPK following TLR4 engagement. GSK3beta inhibitors BIO (6-bromoindirubin-3'-oxime), SB216763, or siRNA knockdown of GSK3beta, but not the PI3K/AKT inhibitor LY294002, prevented Thr172-AMPK dephosphorylation. Exposure to LPS resulted in rapid binding between IKKbeta and AMPKalpha, and phosphorylation of S485-AMPK by IKKbeta. These results suggest that IKKbeta-dependent phosphorylation of S485-AMPK was an essential step in subsequent phosphorylation and inactivation AMPK by GSK3beta. Inhibition of GSK3beta activity delayed IkappaBalpha degradation and diminished expression of the proinflammatory TNF-alpha in LPS-stimulated neutrophils and macrophages. In vivo, inhibition of GSK3beta decreased the severity of LPS-induced lung injury as assessed by development of pulmonary edema, production of TNF-alpha and MIP-2, and release of the alarmins HMGB1 and histone 3 in the lungs. These results show that inhibition of AMPK by GSK3beta plays an important contributory role in enhancing LPS-induced inflammatory responses, including worsening the severity of ALI. |
