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Am J Physiol Gastrointest Liver Physiol 294: G938-G947, 2008. First published February 7, 2008; doi:10.1152/ajpgi.00469.2007
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INFLAMMATION/IMMUNITY/MEDIATORS

Dynamics of enterocyte tight junctions: effect of experimental colitis and two different anti-TNF strategies

Walter Fries,1 Carmelo Muja,2 Carmela Crisafulli,2 Salvatore Cuzzocrea,2,3 and Emanuela Mazzon2,3

1Dipartimento di Medicina Interna e Terapia Medica; 2Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, Sezione di Farmacologia, Università di Messina; and 3Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi "Bonino-Pulejo," Messina, Italy

Submitted 10 October 2007 ; accepted in final form 2 February 2008

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.

infliximab; etanercept; occludin; zonula occludens-1; claudin-2


Address for reprint requests and other correspondence: W. Fries, Dipartimento di Medicina Interna e Terapia Medica, Policlinico Universitario, Pad C, III piano, Via Consolare Valeria, 1, 98100 Messina, Italy (e-mail: walter.fries{at}unime.it)






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