title: Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins.
abstract: Tight junctions (TJs) are dynamic, multiprotein intercellular adhesive contacts that provide a vital barrier function in epithelial tissues. TJs are remodeled during physiological development and pathological mucosal inflammation, and differential expression of the claudin family of TJ proteins determines epithelial barrier properties. However, the molecular mechanisms involved in TJ remodeling are incompletely understood. Using acGFP-claudin 4 as a biosensor of TJ remodeling, we observed increased claudin 4 fluorescence recovery after photobleaching (FRAP) dynamics in response to inflammatory cytokines. Interferon γ and tumor necrosis factor α increased the proportion of mobile claudin 4 in the TJ. Up-regulation of claudin 4 protein rescued these mobility defects and cytokine-induced barrier compromise. Furthermore, claudins 2 and 4 have reciprocal effects on epithelial barrier function, exhibit differential FRAP dynamics, and compete for residency within the TJ. These findings establish a model of TJs as self-assembling systems that undergo remodeling in response to proinflammatory cytokines through a mechanism of heterotypic claudin-binding incompatibility.
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Capaldo
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Attila E
authors.initials: AE
authors.lastname: Farkas
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Hilgarth
authors.affiliation: Institute of Clinical Physiology Charité, Campus Benjamin Franklin, Freie Universität and Humboldt-Universität, 12200 Berlin, Germany.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Krug
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Mattie F
authors.initials: MF
authors.lastname: Wolf
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Benedik
authors.affiliation: Institute of Clinical Physiology Charité, Campus Benjamin Franklin, Freie Universität and Humboldt-Universität, 12200 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Cell Biology, Emory University, Atlanta, GA 30322.
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322.
authors.forename: Charles
authors.initials: C
authors.lastname: Parkos
authors.affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 anusrat@emory.edu.
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
mesh_terms: D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D062506:Claudin-4 / Q000378:metabolism*; D057167:Claudins / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D055503:Protein Multimerization; D019108:Tight Junctions / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C491875:CLDN2 protein, human; C568157:CLDN4 protein, human; D062506:Claudin-4; D057167:Claudins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma