Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis: mechanisms beyond neutralization?
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.
Shen
Chong
C
Laboratory of Experimental Immunology, Katholike Universiteit Leuven, Belgium.
de Hertogh
Gert
G
Bullens
Dominique M A
DM
Van Assche
Gert
G
Geboes
Karel
K
Rutgeerts
Paul
P
Ceuppens
Jan L
JL
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*
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