title: Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form.
abstract: OBJECTIVE
  Tumor necrosis factor (TNF) is cleaved proteolytically from a 26-kilodalton transmembrane precursor protein into secreted 17-kilodalton monomers. Transmembrane (tm) and secreted trimeric TNF are biologically active and may mediate distinct activities. We assessed the consequences of a complete inhibition of TNF processing on the course of colitis in recombination activating gene (RAG)2 -/- mice on transfer of CD4 CD45RB hi T cells.
  
  
  METHODS
  TNF -/- mice, transgenic for a noncleavable mutant TNF gene, were used as donors of CD4 T cells, and, on a RAG2 -/- background, also as recipients. Kinetics of disease development were compared in the absence of TNF, in the absence of secreted TNF, and in the presence of secreted and tmTNF. The analysis at the end of the observation period included the histopathologic assessment of the intestine and the localization of TNF and interferon gamma (IFNgamma)-expressing cells.
  
  
  RESULTS
  The complete prevention of TNF secretion in tmTNF transgenic RAG2 -/- mice neither prevented nor delayed disease induction by transferred transgenic for a noncleavable transmembrane mutant of mouse TNF (tmTNF tg) CD4 CD45RB hi T cells. tmTNF expression by transferred CD4 T cells, however, was not required for disease induction because severe colitis and weight loss also were observed in tmTNF RAG2 -/- recipients of TNF -/- CD4 CD45RB hi T cells. In the presence of tmTNF, the absence of secreted TNF did not affect frequency and distribution of TNF and interferon-gamma messenger RNA (mRNA)-expressing cells.
  
  
  CONCLUSIONS
  These results indicate that specific inhibitors of TNF processing are not appropriate for modulating the pro-inflammatory and disease-inducing effects of TNF in chronic inflammatory disorders of the intestine.
authors.affiliation: Department of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Nadia
authors.initials: N
authors.lastname: Corazza
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.forename: Caroline
authors.initials: C
authors.lastname: Buri
authors.forename: Silvia
authors.initials: S
authors.lastname: Rihs
authors.forename: Martin A
authors.initials: MA
authors.lastname: Imboden
authors.forename: Inge
authors.initials: I
authors.lastname: Seibold
authors.forename: Christoph
authors.initials: C
authors.lastname: Mueller
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D003092:Colitis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D018014:Gene Transfer Techniques; D007413:Intestinal Mucosa / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C064655:V(D)J recombination activating protein 2; D017493:Leukocyte Common Antigens