期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 204, 期 7, 页码 1637-1652出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20062621
关键词
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资金
- NIAID NIH HHS [R01 AI050179, AI 68088, R01 AI068088, AI 50179, AI 597119] Funding Source: Medline
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-KB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-KB 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 x mediates nuclear export of p65. By reducing I kappa B alpha level, MK2 prevents premature export of NF-KB from the nucleus. Thus, the MK2-HSP27 pathway regulates the NF-KB 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.
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