title: Stress-Derived Corticotropin Releasing Factor Breaches Epithelial Endotoxin Tolerance.
abstract: Loss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance.
  
  
  
  Epithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine.
  
  
  
  The established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2.
  
  
  
  Psychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa.
authors.affiliation: Department of Gastroenterology, the Second Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Liu
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Xiao-Rui
authors.initials: XR
authors.lastname: Geng
authors.forename: Gui
authors.initials: G
authors.lastname: Yang
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Liu
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Zheng
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D057167:Claudins / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D004351:Drug Resistance; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019073:HT29 Cells; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D013315:Stress, Psychological / Q000139:chemically induced / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003346:Corticotropin-Releasing Hormone