Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis: mechanisms beyond neutralization?

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-fluoromethylketone (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.

• Authors: Chong Shen, Gert de Hertogh, Dominique M A Bullens, Gert Van Assche, Karel Geboes, Paul Rutgeerts, Jan L Ceuppens
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 13 Issue 3 Pg. 308-16 (Mar 2007) ISSN: 1078-0998 [Print] England
• PMID: 17206708 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antibodies, Monoclonal
• Caspase Inhibitors
• Interleukin-18
• Tumor Necrosis Factor-alpha
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Oxazolone
• Interferon-gamma
• Trinitrobenzenesulfonic Acid
• Infliximab

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Apoptosis (drug effects)
• Caspase Inhibitors
• Colitis (chemically induced)
• Down-Regulation
• Inflammatory Bowel Diseases (drug therapy, immunology, physiopathology)
• Infliximab
• Interferon-gamma (metabolism)
• Interleukin-18 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oxazolone
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)