Vandendriessche, BenjaminGoethals, AnSimats, AlbaHamme, Evelien VanBrouckaert, PeterCauwels, Anje2015-03-242015-03-242014Vandendriessche B, Goethals A, Simats A, Van Hamme E, Brouckaert P, Cauwels A. MAPK-activated protein kinase 2-deficiency causes hyperacute tumor necrosis factor-induced inflammatory shock. BMC Physiology. 2014;14:5. DOI: 10.1186/s12899-014-0005-11472-6793http://hdl.handle.net/10230/23266Background: 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.application/pdfeng© 2014 Vandendriessche et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Proteïnes quinasesRegulació cel·lularRNA missatgerinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/s12899-014-0005-1MK2Inflammatory shockTumor necrosis factorReactive oxygen speciesActin cytoskeletonEndothelial permeabilityCecal ligation and punctureinfo:eu-repo/semantics/openAccess