title: Effect of genetic deletion or pharmacological antagonism of tumor necrosis factor alpha on colitis-associated carcinogenesis in mice.
abstract: BACKGROUND
  Intestinal inflammation in inflammatory bowel diseases is driven by abnormal levels of proinflammatory cytokines, where tumor necrosis factor (TNF)-α seems to be particularly important. Chronic inflammatory signaling in the colon increases the risk of colorectal cancer, so we sought to evaluate the role of TNF-α in a mouse model of this condition.
  
  
  METHODS
  TNF mice were treated with azoxymethane/dextran sulfate sodium to induce inflammation and tumorigenesis. Etanercept was used to produce pharmacological ablation of TNF-α in wild-type mice. Subsequent activation of procarcinogenic transcription factor NF-κB and relevant proinflammatory cytokines of the TNF superfamily were measured through immunohistochemistry and quantitative polymerase chain reaction methods.
  
  
  RESULTS
  Results showed that the severity of colitis, as assessed by mortality, histological scoring, and cytokine expression levels, was similar or slightly higher in mice lacking TNF-α than in control mice. Activation levels of NF-κB were not influenced by the presence of TNF-α. We also observed upregulated expression of TNF family member TNF-β, TNF receptors 1 and 2 and a variety of other proinflammatory factors in colitis-associated tumors of TNF mice, compared with levels in tumors of control mice. Neither genetic ablation of TNF-α nor pharmacological inhibition of the TNF family using etanercept reduced tumor number.
  
  
  CONCLUSIONS
  Our results reveal a redundant role for TNF-α in a mouse model of colitis-associated tumorigenesis, indicating a high degree of redundancy in proinflammatory cytokine networks in this model.
authors.affiliation: Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Craven
authors.forename: Violeta
authors.initials: V
authors.lastname: Zaric
authors.forename: Abigail
authors.initials: A
authors.lastname: Martin
authors.forename: Coralie
authors.initials: C
authors.lastname: Mureau
authors.forename: Laurence John
authors.initials: LJ
authors.lastname: Egan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D000068800:Etanercept / Q000494:pharmacology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D001397:Azoxymethane; D000068800:Etanercept