title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Laboratory of Experimental Immunology, Katholike Universiteit Leuven, Belgium.
authors.forename: Chong
authors.initials: C
authors.lastname: Shen
authors.forename: Gert
authors.initials: G
authors.lastname: de Hertogh
authors.forename: Dominique M A
authors.initials: DM
authors.lastname: Bullens
authors.forename: Gert
authors.initials: G
authors.lastname: Van Assche
authors.forename: Karel
authors.initials: K
authors.lastname: Geboes
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Jan L
authors.initials: JL
authors.lastname: Ceuppens
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D003092:Colitis / Q000139:chemically induced; D015536:Down-Regulation; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D000069285:Infliximab; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010081:Oxazolone; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D010081:Oxazolone; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; D000069285:Infliximab