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.