Program in Molecular Medicine
Animals; Disease Models, Animal; Drug-Induced Liver Injury; Gene Expression Regulation; HEK293 Cells; Humans; Lipopolysaccharides; MAP Kinase Kinase 3; MAP Kinase Kinase 6; MAP Kinase Signaling System; Macrophages; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 12; Mitogen-Activated Protein Kinase 13; Peptide Chain Elongation, Translational; Peptide Elongation Factor 2; Tumor Necrosis Factor-alpha
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-alpha. TNF-alpha 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-alpha 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 p38gamma/delta MAPK proteins is required for the elongation of nascent TNF-alpha protein in macrophages. The MKK3/6-p38gamma/delta pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-alpha elongation. These results identify a new signaling pathway that regulates TNF-alpha production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-alpha production is involved.
Rights and Permissions
Publisher PDF posted as allowed by the publisher's author rights policy. See http://content-assets.jci.org/admin/forms/jcicopyright.pdf
DOI of Published Version
J Clin Invest. 2013 Jan;123(1):164-78. doi: 10.1172/JCI65124. Epub 2012 Dec 3. Link to article on publisher's site
The Journal of clinical investigation
Gonzalez-Teran, Barbara; Cortes, Jose R.; Manieri, Elisa; Matesanz, Nuria; Verdugo, Angeles; Rodriguez, Maria E.; Gonzalez-Rodriguez, Agueda; Valverde, Angela M.; Martin, Pilar; Davis, Roger J.; and Sabio, Guadalupe, "Eukaryotic elongation factor 2 controls TNF-alpha translation in LPS-induced hepatitis" (2013). Davis Lab Publications. 3.