title: Disruption of epithelial barrier by quorum-sensing N-3-(oxododecanoyl)-homoserine lactone is mediated by matrix metalloproteinases.
abstract: The intestinal epithelium forms a selective barrier maintained by tight junctions (TJs) and separating the luminal environment from the submucosal tissues. N-acylhomoserine lactone (AHL) quorum-sensing molecules produced by gram-negative bacteria in the gut can influence homeostasis of the host intestinal epithelium. In the present study, we evaluated the regulatory mechanisms affecting the impact of two representative long- and short-chain AHLs, N-3-(oxododecanoyl)-homoserine lactone (C12-HSL) and N-butyryl homoserine lactone (C4-HSL), on barrier function of human intestinal epithelial Caco-2 cells. Treatment with C12-HSL, but not with C4-HSL, perturbed Caco-2 barrier function; the effect was associated with decreased levels of the TJ proteins occludin and tricellulin and their delocalization from the TJs. C12-HSL also induced matrix metalloprotease (MMP)-2 and MMP-3 activation via lipid raft- and protease-activated receptor (PAR)-dependent signaling. Pretreatment with lipid raft disruptors, PAR antagonists, or MMP inhibitors restored the C12-HSL-induced loss of the TJ proteins and increased permeability of Caco-2 cell monolayers. These results indicate that PAR/lipid raft-dependent MMP-2 and -3 activation followed by degradation of occludin and tricellulin are involved in C12-HSL-induced alterations of epithelial paracellular barrier functions.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Eum
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and.
authors.forename: Dima
authors.initials: D
authors.lastname: Jaraki
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and.
authors.forename: Ibolya E
authors.initials: IE
authors.lastname: András
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and Jerzy Kukuczka Academy of Physical Education, Katowice, Poland mtoborek@med.miami.edu.
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D054742:Acyl-Butyrolactones / Q000494:pharmacology; D018938:Caco-2 Cells; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation; D006714:Homoserine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology*; D007783:Lactones / Q000494:pharmacology*; D062794:MARVEL Domain Containing 2 Protein / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000502:physiology; D062793:Occludin / Q000378:metabolism; D010539:Permeability; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: D054742:Acyl-Butyrolactones; D007783:Lactones; D062794:MARVEL Domain Containing 2 Protein; D062793:Occludin; D062725:Tight Junction Proteins; C085113:Pseudomonas aeruginosa autoinducer; D006714:Homoserine; D020782:Matrix Metalloproteinases
keywords: N-acylhomoserine lactone; intestinal epithelium; matrix metalloprotease; occludin; tricellulin
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