Infliximab and etanercept are equally effective in reducing enterocyte APOPTOSIS in experimental colitis.
Loss of epithelial barrier integrity is considered an early step in the pathogenesis of Crohn's disease (CD), and the rate of enterocyte apoptosis is one of the determinants of the intestinal barrier function. Tumor necrosis factor-alpha (TNF-alpha), one of the major proinflammatory mediators in CD, is one of the extrinsic signals which initiate apoptosis of enterocytes. The aim of this study was to investigate the early effects of experimental colitis on enterocyte apoptosis, and the effects of two anti-TNF treatments, infliximab (IFX) and etanercept (ETC). In addition, the importance of receptor I for TNF was tested in TNFR-1(-/- )mice. Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h. Apoptosis of the ileal enterocytes, assessed by TUNEL staining, staining for Fas-ligand, and bax, increased at 3 and 6h. These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals. The anti-apoptotic protein Bcl-2 was expressed in the ileal epithelium under control conditions, but was suppressed in DNB-colitis. Expression of Bcl-2 was maintained in both anti-TNF treatments and TNFR-1(-/-) mice.DNB colitis induced a very early, rapid increase of enterocyte apoptosis. Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.
Fries
Walter
W
Dipartimento di Medicina Interna e Terapia Medica, Sezione di Farmacologia, Università di Messina, Messina, Italy. fwalter@unime.it
Muja
Carmelo
C
Crisafulli
Carmela
C
Costantino
Giuseppe
G
Longo
Giuseppe
G
Cuzzocrea
Salvatore
S
Mazzon
Emanuela
E
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068800:Etanercept; D053222:Fas Ligand Protein / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000069285:Infliximab; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D001557:Benzenesulfonates; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C007488:dinitrobenzenesulfonic acid; D000069285:Infliximab; D000068800:Etanercept