Dynamics of enterocyte tight junctions: effect of experimental colitis and two different anti-TNF strategies.
An alteration of the intestinal barrier is considered to represent an early step in pathogenesis of Crohn's disease. The integrity of intestinal barrier function is guaranteed among other factors by enterocyte tight junction (TJ) proteins. Clinical and experimental data indicate the TNF-alpha to be the major responsible factor for these defects. In the present study we investigated the very early effects of DNBS-ethanol colitis on ileal enterocyte TJ proteins [occludin, zonula occludens-1 (ZO-1), claudin-2] in controls, mice treated with infliximab (IFX) or with etanercept (ETC), and in knockout mice for the TNF-alpha receptor 1 (TNFR-1(-/-)). Circulating TNF-alpha levels were effectively reduced by IFX and ETC (P < 0.01, both) at 3 and at 6 h. DNBS colitis induced disappearance of occludin and ZO-1 from enterocyte cell-cell contact, whereas claudin-2, absent under control conditions, appeared in the ileal epithelium. These alterations were prevented equally by both treatments, IFX and ETC, and in TNFR-1(-/-) animals. DNBS colitis induced a very rapid loss of occludin and ZO-1 from ileal TJ together with an upregulation of claudin-2. Our data are consistent with the hypothesis that TNF-alpha is involved in early TJ rearrangement and that its effects are mediated through TNFR-1. Despite clinical differences, both anti-TNF treatments were equally effective in the present setting.
Fries
Walter
W
Dipartimento di Medicina Interna e Terapia Medica, Policlinico Universitario, Pad C, III piano, Via Consolare Valeria, 1, 98100 Messina, Italy. walter.fries@unime.it
Muja
Carmelo
C
Crisafulli
Carmela
C
Cuzzocrea
Salvatore
S
Mazzon
Emanuela
E
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D001557:Benzenesulfonates; D057167:Claudins; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068800:Etanercept; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D000069285:Infliximab; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D001557:Benzenesulfonates; D057167:Claudins; C113371:Cldn2 protein, mouse; D005765:Gastrointestinal Agents; D007074:Immunoglobulin G; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C569043:Tjp1 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; C007488:dinitrobenzenesulfonic acid; D000069285:Infliximab; D000068800:Etanercept