Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice

Eur J Immunol. 1997 Jul;27(7):1743-50. doi: 10.1002/eji.1830270722.


Antibodies to tumor necrosis factor (TNF)-alpha have been recently proposed as effective treatment for patients with Crohn's disease. Here, we analyze the functional role of TNF-alpha in a mouse model of chronic intestinal inflammation induced by the hapten reagent 2,4,6,-trinitrobenzene sulfonic acid (TNBS) that mimics some characteristics of Crohn's disease in humans. Macrophage-enriched lamina propria (LP) mononuclear cells from mice with TNBS-induced colitis produced 10-30-fold higher levels of TNF-alpha mRNA and protein than cells from control mice. When mice with chronic colitis were treated by intraperitoneal injection of antibodies to TNF-alpha, an improvement of both the clinical and histopathologic signs of disease was found. Isolated macrophage-enriched LP cells from anti-TNF-alpha-treated mice produced strikingly less pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 in cell culture. The predominant role of TNF-alpha in the mouse TNBS-induced colitis model was further underlined by the finding that striking colonic inflammation and lethal pancolitis was induced in TNF-alpha-transgenic mice upon TNBS treatment. Conversely, no significant TNBS-induced colitis could be induced in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Complementation of TNF-alpha function in TNF-/- mice by the expression of a mouse TNF-alpha transgene was sufficient to reverse this effect. Taken together, the data provide direct evidence for a predominant role of TNF-alpha in a mouse model of chronic intestinal inflammation and encourage further clinical trials with antibodies to TNF-alpha for the treatment of patients with Crohn's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • Chronic Disease
  • Colitis / etiology*
  • Colitis / immunology*
  • Colitis / mortality
  • Colitis / pathology
  • Disease Models, Animal
  • Female
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / pathology
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, Transgenic
  • Trinitrobenzenesulfonic Acid / toxicity
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / physiology*


  • Antibodies
  • Tumor Necrosis Factor-alpha
  • Trinitrobenzenesulfonic Acid