title: 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.
authors.affiliation: Division of Allergy and Immunology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Liang
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Stafford
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goplen
authors.forename: Nilesh
authors.initials: N
authors.lastname: Dharajiya
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Sur
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: 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
chemical_list: 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