title: Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis.
abstract: Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.
authors.affiliation: Department of Vascular Biology and Inflammation, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: González-Terán
authors.forename: José R
authors.initials: JR
authors.lastname: Cortés
authors.forename: Elisa
authors.initials: E
authors.lastname: Manieri
authors.forename: Nuria
authors.initials: N
authors.lastname: Matesanz
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Verdugo
authors.forename: María E
authors.initials: ME
authors.lastname: Rodríguez
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
authors.forename: Ángela
authors.initials: Á
authors.lastname: Valverde
authors.forename: Pilar
authors.initials: P
authors.lastname: Martín
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Sabio
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects* / Q000235:genetics; D020652:Peptide Elongation Factor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D020652:Peptide Elongation Factor 2; D014409:Tumor Necrosis Factor-alpha; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse