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Title: Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis: Mechanisms beyond neutralization?
Authors: Shen, Chong ×
De Hertogh, Gert
Bullens, Dominique
Van Assche, Gert
Geboes, Karel
Rutgeerts, Paul
Ceuppens, Jan #
Issue Date: 2007
Series Title: Inflammatory Bowel Diseases vol:13 issue:3 pages:308-316
Abstract: Background: Tumor necrosis factor (TNF) plays an important role in the pathogenesis of several inflammatory diseases. Its expression is increased in inflamed mucosa of Crohn's disease patients and anti-TNF treatment improves mucosal inflammation. Besides neutralization, induction of apoptosis of monocytes/macrophages and T cells is thought to be an important mechanism of action of the anti-TNF monoclonal antibody therapy. The aim was to investigate the pathogenic role of TNF in hapten-induced colitis models and to study the relationship between apoptosis induction and disease remission.Methods: In 2 murine colitis models (trinitrobenzene sulphonic acid, TNBS, and oxazolone colitis), mice were injected daily with anti-TNF monoclonal antibody (mAb). Macrophages were collected from lamina propria of TNBS colitis mice. 7AAD and anti-active-caspase-3 staining were used to study DNA degradation and intracellular caspase activation. A pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone (Z-VAD-FMK), was given to a subgroup of the colitis mice.Results: Treatment with anti-TNF effectively reduced intestinal mucosal inflammation in TNBS colitis but not in oxazolone colitis. Effectiveness was evidenced by a more rapid recovery of body weight and reduced cell infiltration, and downregulation of proinflammatory cytokines interferon-gamma (IFN-gamma), TNF, and IL-18 at the mRNA level. Apoptosis was induced in lamina propria macrophages after treatment with anti-TNF, and it was abrogated through short-term pretreatment with Z-VAD-FMK.Conclusion: Anti-TNF downregulates proinflammatory cytokines and decreases cell infiltration in the bowel after TNBS application. The remission-inducing effect of anti-TNF may partly rely on apoptosis induction.(Inflamm Bowel Dis 2006).
Description: Afdeling Morfologie en moleculaire pathologie. Afdeling Klinische immunologie. Afdeling Gastro-enterologie.
ISSN: 1078-0998
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Cell & Tissue Research
Laboratory of Clinical Immunology
Translational Research in GastroIntestinal Disorders
Laboratory of Pediatric Immunology
× corresponding author
# (joint) last author

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