10.25358/DSPACE-DEV-82224
Neurath, Markus F.
Fuss, Ivan J.
Pasparakis, Manolis
Alexopoulou, Lena
Haralambous, Sylva
Meyer zum Büschenfelde, Karl-Hermann
Strober, Warren
Kollias, George
Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice
Johannes Gutenberg-Universität Mainz
1997
610 Medizin
610 Medical sciences Medicine
Johannes Gutenberg-Universität Mainz
Johannes Gutenberg-Universität Mainz
2020-03-12
2020-03-12
1997
Zeitschriftenaufsatz
European journal of immunology. Bd. 27. H. 7. Weinheim : Wiley. S. 1743 - 1750
https://dspace-dev.ub.uni-mainz.de/handle/20.500.12030/135275
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.