title: Mechanism of interleukin-1β induced-increase in mouse intestinal permeability in vivo.
abstract: Interleukin-1β (IL-1β) has been shown to play an essential role in mediating intestinal inflammation of Crohn's disease and other inflammatory conditions of the gut. Previous studies from our laboratory have shown that IL-1β causes an increase in intestinal tight-junction permeability in Caco-2 monolayers in vitro. However, the IL-1β effect on the intestinal epithelial barrier in vivo remains unclear.
  
  
  OBJECTIVE
  the major aims of this study were to examine the effect of IL-1β on mouse intestinal epithelial barrier in vivo and to delineate the mechanisms involved using an in vivo model system consisting of a recycling perfusion of mouse small intestine. Intraperitonial injection of IL-1β at varying doses (0-10 μg) caused a concentration-dependent increase in mouse intestinal permeability to the paracellular marker dextran (10 KD), and the maximal increase in dextran flux occurred at IL-1β dose of 5 μg. IL-1β treatment caused an increase in myosin light-chain kinase (MLCK) mRNA and protein expression in the small intestinal tissue starting at 24 h, which continued up to 72 h. Additionally, IL-1β did not cause an increase in intestinal permeability in MLCK-deficient mice (C57BL/6 MLCK(-/-)). MLCK inhibitor ML-7 (2 mg/kg body weight) also inhibited the IL-1β-induced increase in small intestinal permeability. The IL-1β-induced increase in mouse intestinal permeability was associated with an increase in NF-κB activation. The intestinal tissue-specific silencing of NF-κB p65 inhibited the IL-1β-induced increase in intestinal permeability and increase in MLCK expression. These data show for the first time that IL-1β causes an increase in mouse intestinal permeability in vivo. These data suggested that the mechanism of IL-1β-induced increase in mouse intestinal permeability in vivo involved NF-κB p65-induced activation of the mouse enterocyte MLCK gene.
authors: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
authors: Rana
authors: R
authors: Al-Sadi
authors: Shuhong
authors: S
authors: Guo
authors: Karol
authors: K
authors: Dokladny
authors: Matthew A
authors: MA
authors: Smith
authors: Dongmei
authors: D
authors: Ye
authors: Archana
authors: A
authors: Kaza
authors: D Martin
authors: DM
authors: Watterson
authors: Thomas Y
authors: TY
authors: Ma
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D018938:Caco-2 Cells; D003424:Crohn Disease / Q000276:immunology*; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D020895:Enterocytes / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology* / Q000494:pharmacology; D007422:Intestines / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D010539:Permeability; D034741:RNA, Small Interfering / Q000235:genetics; D019108:Tight Junctions / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation
chemical_list: D001381:Azepines; D003911:Dextrans; D053583:Interleukin-1beta; D009281:Naphthalenes; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; C070571:ML 7; D009219:Myosin-Light-Chain Kinase