title: TWEAK/Fn14 pathway: a nonredundant role in intestinal damage in mice through a TWEAK/intestinal epithelial cell axis.
abstract: OBJECTIVE
  Tumor necrosis factor (TNF) superfamily members have attracted attention as new therapeutic targets for treating inflammatory disease. TNF-like weak inducer of apoptosis (TWEAK) is a unique, multifunctional TNF family cytokine that signals through its receptor, fibroblast growth factor-inducible molecule 14 (Fn14). The role of this pathway in the intestine has not been previously reported.
  
  
  METHODS
  The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model was conducted in TWEAK- or Fn14-deficient mice or in normal mice treated with a TWEAK-blocking monoclonal antibody, and clinical severity, histopathology, immunohistochemistry for cell infiltrates, TWEAK and Fn14, gene expression profiling in the colon, and systemic adaptive immunity were assessed. The effect of TWEAK on colon epithelial cell production of inflammatory mediators was analyzed in vitro. The gamma-irradiation injury model was conducted in TWEAK- or Fn14-deficient mice, and crypt epithelial death was assessed.
  
  
  RESULTS
  Colitis severity and histologic scores were significantly reduced by TWEAK pathway deficiency or TWEAK-blocking monoclonal antibody. Neutrophil and macrophage infiltrates, chemokines, cytokines, and matrix metalloproteinase expression were reduced in the TWEAK-deficient colon after TNBS administration; however, systemic adaptive immune responses to trinitrophenyl were not altered. Fn14 is expressed on colon epithelial cells in TNBS colitis, and TWEAK induces epithelial production of pathogenic mediators. TWEAK also regulates intestinal epithelial turnover, as evidenced by reduced epithelial cell death after gamma-irradiation injury in TWEAK and Fn14 knockout mice.
  
  
  CONCLUSIONS
  Our studies elucidate a nonredundant TWEAK-intestinal epithelial cell axis and suggest that blocking TWEAK may dampen chronic intestinal inflammation and allow normal epithelial repair.
authors.affiliation: Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Dohi
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Shearstone
authors.forename: Rei
authors.initials: R
authors.lastname: Kawashima
authors.forename: Laura
authors.initials: L
authors.lastname: Runkel
authors.forename: Luis
authors.initials: L
authors.lastname: Rajman
authors.forename: Xingwen
authors.initials: X
authors.lastname: Dong
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.forename: Aniela
authors.initials: A
authors.lastname: Jakubowski
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005720:Gamma Rays; D007107:Immune System / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D014456:Ulcer / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000074049:Cytokine TWEAK; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors