title: Toll-like receptor 4 engagement inhibits adenosine 5'-monophosphate-activated protein kinase activation through a high mobility group box 1 protein-dependent mechanism.
abstract: Despite the potent antiinflammatory effects of pharmacologically induced adenosine 5'-monophosphate kinase (AMPK) activation on Toll-like receptor 4 (TLR4)-induced cellular activation, there is little evidence that AMPK is activated during inflammatory conditions. In the present studies, we examined mechanisms by which TLR4 engagement may affect the ability of AMPK to become activated in neutrophils and macrophages under in vitro conditions and in the lungs during lipopolysaccharide (LPS)-induced acute lung injury. We found that incubation of neutrophils or macrophages with LPS diminished the ability of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) or hydrogen peroxide (H(2)O(2)) to activate AMPK. Although ratios of AMP to adenosine 5'-triphosphate (ATP) were increased in LPS-treated neutrophils and in the lungs of LPS exposed mice, a condition that should result in AMPK activation, no activation of AMPK was found. Immunocytochemistry and Western blot analysis revealed that nuclear to cytosolic translocation of the proinflammatory mediator high mobility group box 1 protein (HMGB1) correlated with inhibition of AMPK activation in LPS-stimulated macrophages. Moreover, while induced overexpression of HMGB1 resulted in inhibition of AMPK activation, Small interfering RNA (siRNA)-induced knockdown of HMGB1 was associated with enhanced activation of AMPK in macrophages incubated with AICAR. Increased interaction between liver kinase B1 (LKB1), an upstream activator of AMPK, and HMGB1 was found in LPS-stimulated macrophages and in the lungs of mice exposed to LPS. These results suggest that nuclear to cytoplasmic translocation of HMGB1 in TLR4-activated cells potentiates inflammatory responses by binding to LKB1, thereby inhibiting the antiinflammatory effects of AMPK activation.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tadie
authors.forename: Hong-Beom
authors.initials: HB
authors.lastname: Bae
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
authors.forename: Celeste P
authors.initials: CP
authors.lastname: Bell
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Lazarowski
authors.forename: David D
authors.initials: DD
authors.lastname: Chaplin
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases