title: TNF-α modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1.
abstract: Tumor necrosis factor (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of inflammatory bowel disease. TNF-α causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of MAP kinase pathways (ERK1/2 and p38 kinase) and the molecular processes involved. An in vitro intestinal epithelial model system consisting of Caco-2 monolayers and an in vivo mouse model system were used to delineate the cellular and molecular mechanisms involved in TNF-α effects on tight junction barrier. The TNF-α-induced increase in Caco-2 tight junction permeability was mediated by activation of the ERK1/2 signaling pathway, but not the p38 kinase pathway. Activation of the ERK1/2 pathway led to phosphorylation and activation of the ETS domain-containing transcription factor Elk-1. The activated Elk-1 translocated to the nucleus, where it bound to its binding motif on the myosin light chain kinase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. In addition, in vivo intestinal perfusion studies also indicated that the TNF-α-induced increase in mouse intestinal permeability requires ERK1/2-dependent activation of Elk-1. These studies provide novel insight into the cellular and molecular processes that regulate the TNF-α-induced increase in intestinal epithelial tight junction permeability.
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Rana
authors.initials: R
authors.lastname: Al-Sadi
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico. Electronic address: tma@salud.unm.edu.
authors.forename: Thomas Y
authors.initials: TY
authors.lastname: Ma
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D018938:Caco-2 Cells; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D011401:Promoter Regions, Genetic / Q000502:physiology; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D050807:ets-Domain Protein Elk-1; D009219:Myosin-Light-Chain Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3