MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation

Magdalena M. Gorska, Qiaoling Liang, Susan J. Stafford, Nicolas Goplen, Nilesh Dharajiya, Lei Guo, Sanjiv Sur, Matthias Gaestel, Rafeul Alam

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73 Scopus citations

Abstract

We demonstrate that mitogen-activated protein kinase-activated kinase-2 (MK2) is essential for localized Th2-type inflammation and development of experimental asthma. MK2 deficiency does not affect systemic Th2 immunity, but reduces endothelial permeability, as well as adhesion molecule and chemokine expression. NF-κB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-κB activation. MK2 and HSP27 prevent nuclear retention of p38 by sequestering it in the cytosol. As a result, MK2 precludes excessive phosphorylation of MSK1. By reducing MSK1 activity, MK2 prevents p65 NF-κB hyperphosphorylation and excessive IκBα transcription. IκBα mediates nuclear export of p65. By reducing IκBα level, MK2 prevents premature export of NF-κB from the nucleus. Thus, the MK2-HSP27 pathway regulates the NF-κB transcriptional output by switching the activation pattern from high level, but short lasting, to moderate-level, but long lasting. This pattern of activation is essential for many NF-κB-regulated genes and development of inflammation. Thus, the MK2-HSP27 pathway is an excellent target for therapeutic control of localized inflammatory diseases. JEM

Original languageEnglish (US)
Pages (from-to)1637-1652
Number of pages16
JournalJournal of Experimental Medicine
Volume204
Issue number7
DOIs
StatePublished - Jul 9 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Gorska, M. M., Liang, Q., Stafford, S. J., Goplen, N., Dharajiya, N., Guo, L., Sur, S., Gaestel, M., & Alam, R. (2007). MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation. Journal of Experimental Medicine, 204(7), 1637-1652. https://doi.org/10.1084/jem.20062621