The Journal of Experimental Medicine
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Published online June 18, 2007
doi:10.1084/jem.20062621
The Journal of Experimental Medicine, Vol. 204, No. 7, 1637-1652
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Gorska et al.
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ARTICLE

 MK2 controls the level of negative feedback in the NF-{kappa}B pathway and is essential for vascular permeability and airway inflammation

Magdalena M. Gorska1, Qiaoling Liang1, Susan J. Stafford2, Nicolas Goplen1, Nilesh Dharajiya2, Lei Guo1, Sanjiv Sur2, Matthias Gaestel3, and Rafeul Alam1

1 Division of Allergy and Immunology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206
2 Division of Allergy and Immunology, Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555
3 Institute of Biochemistry, Hannover Medical School, 30625 Hannover, Germany

CORRESPONDENCE Rafeul Alam: alamr{at}njc.org

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-{kappa}B regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-{kappa}B 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-{kappa}B hyperphosphorylation and excessive I{kappa}B{alpha} transcription. I{kappa}B{alpha} mediates nuclear export of p65. By reducing I{kappa}B{alpha} level, MK2 prevents premature export of NF-{kappa}B from the nucleus. Thus, the MK2–HSP27 pathway regulates the NF-{kappa}B 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-{kappa}B–regulated genes and development of inflammation. Thus, the MK2–HSP27 pathway is an excellent target for therapeutic control of localized inflammatory diseases.

Abbreviations used: AHR, airway hyperresponsiveness; AU, arbitrary unit; BAL, bronchoalveolar lavage; BM, basement membrane; CREB, cAMP response element binding protein; ECM, extracellular matrix; EGF, epidermal growth factor; HE, hematoxylin and eosin; HUVEC, human umbilical vein endothelial cell; ICAM, intercellular adhesion molecule; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; MK, MAPK-activated kinase; MNC, mononuclear cell; PAS, periodic acid-Schiff; VCAM, vascular cell adhesion molecule.


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