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MK2 controls the level of negative feedback in the NF-kappaB 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-kappaB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-kappaB 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-kappaB hyperphosphorylation and excessive IkappaBalpha transcription. IkappaBalpha mediates nuclear export of p65. By reducing IkappaBalpha level, MK2 prevents premature export of NF-kappaB from the nucleus. Thus, the MK2-HSP27 pathway regulates the NF-kappaB 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-kappaB-regulated genes and development of inflammation. Thus, the MK2-HSP27 pathway is an excellent target for therapeutic control of localized inflammatory diseases.

SUBMITTER: Gorska MM 

PROVIDER: S-EPMC2118652 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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

Gorska Magdalena M MM   Liang Qiaoling Q   Stafford Susan J SJ   Goplen Nicolas N   Dharajiya Nilesh N   Guo Lei L   Sur Sanjiv S   Gaestel Matthias M   Alam Rafeul R  

The Journal of experimental medicine 20070625 7


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-kappaB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-kappaB activation. MK2 and HSP27 prevent n  ...[more]

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