MK2 controls the level of negative feedback in the NF-kappaB pathway and is essential for vascular permeability and airway inflammation.
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.
Gorska
Magdalena M
MM
Division of Allergy and Immunology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
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
D019264:Adoptive Transfer; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D004730:Endothelium, Vascular / Q000502:physiology; D005246:Feedback; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D012140:Respiratory Tract Diseases / Q000276:immunology / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection; D014471:Umbilical Veins / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000099190:MAP-Kinase-Activated Kinase 2; C486699:Hspb2 protein, mouse