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

Research output: Contribution to journalArticle

73 Citations (Scopus)

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

Fingerprint

Capillary Permeability
Chemokines
MAP Kinase Kinase 2
Inflammation
Cell Nucleus Active Transport
Cytosol
Immunity
Permeability
Asthma
Phosphorylation
Genes
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation. / Gorska, Magdalena M.; Liang, Qiaoling; Stafford, Susan J.; Goplen, Nicolas; Dharajiya, Nilesh; Guo, Lei; Sur, Sanjiv; Gaestel, Matthias; Alam, Rafeul.

In: Journal of Experimental Medicine, Vol. 204, No. 7, 09.07.2007, p. 1637-1652.

Research output: Contribution to journalArticle

Gorska, MM, Liang, Q, Stafford, SJ, 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, vol. 204, no. 7, pp. 1637-1652. https://doi.org/10.1084/jem.20062621
Gorska, Magdalena M. ; Liang, Qiaoling ; Stafford, Susan J. ; Goplen, Nicolas ; Dharajiya, Nilesh ; Guo, Lei ; Sur, Sanjiv ; Gaestel, Matthias ; Alam, Rafeul. / MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation. In: Journal of Experimental Medicine. 2007 ; Vol. 204, No. 7. pp. 1637-1652.
@article{38ba016f3e8c4849bb6e456d3c85acc0,
title = "MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation",
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",
author = "Gorska, {Magdalena M.} and Qiaoling Liang and Stafford, {Susan J.} and Nicolas Goplen and Nilesh Dharajiya and Lei Guo and Sanjiv Sur and Matthias Gaestel and Rafeul Alam",
year = "2007",
month = "7",
day = "9",
doi = "10.1084/jem.20062621",
language = "English (US)",
volume = "204",
pages = "1637--1652",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "7",

}

TY - JOUR

T1 - MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation

AU - Gorska, Magdalena M.

AU - Liang, Qiaoling

AU - Stafford, Susan J.

AU - Goplen, Nicolas

AU - Dharajiya, Nilesh

AU - Guo, Lei

AU - Sur, Sanjiv

AU - Gaestel, Matthias

AU - Alam, Rafeul

PY - 2007/7/9

Y1 - 2007/7/9

N2 - 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

AB - 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

UR - http://www.scopus.com/inward/record.url?scp=34447258367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447258367&partnerID=8YFLogxK

U2 - 10.1084/jem.20062621

DO - 10.1084/jem.20062621

M3 - Article

VL - 204

SP - 1637

EP - 1652

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 7

ER -