title: MAPK-activated protein kinase 2-deficiency causes hyperacute tumor necrosis factor-induced inflammatory shock.
abstract: BACKGROUND
  MAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. Among others, MK2 is known to be involved in the regulation of cytokine mRNA metabolism and regulation of actin cytoskeleton dynamics. Previously, MK2-deficient mice were shown to be highly resistant to LPS/d-Galactosamine-induced hepatitis. Additionally, research in various disease models has indicated the kinase as an interesting inhibitory drug target for various acute or chronic inflammatory diseases.
  
  
  RESULTS
  We show that in striking contrast to the known resistance of MK2-deficient mice to a challenge with LPS/D-Gal, a low dose of tumor necrosis factor (TNF) causes hyperacute mortality via an oxidative stress driven mechanism. We identified in vivo defects in the stress fiber response in endothelial cells, which could have resulted in reduced resistance of the endothelial barrier to deal with exposure to oxidative stress. In addition, MK2-deficient mice were found to be more sensitive to cecal ligation and puncture-induced sepsis.
  
  
  CONCLUSIONS
  The capacity of the endothelial barrier to deal with inflammatory and oxidative stress is imperative to allow a regulated immune response and maintain endothelial barrier integrity. Our results indicate that, considering the central role of TNF in pro-inflammatory signaling, therapeutic strategies examining pharmacological inhibition of MK2 should take potentially dangerous side effects at the level of endothelial barrier integrity into account.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vandendriessche
authors.forename: An
authors.initials: A
authors.lastname: Goethals
authors.forename: Alba
authors.initials: A
authors.lastname: Simats
authors.forename: Evelien
authors.initials: E
authors.lastname: Van Hamme
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.affiliation: Inflammation Research Center, VIB, Ghent, 9052, Belgium. anje.cauwels@vib-ugent.be.
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000201:enzymology; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000401:mortality; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000201:enzymology / Q000401:mortality; D022502:Stress Fibers / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2