CIDCA   05380
CENTRO DE INVESTIGACION Y DESARROLLO EN CRIOTECNOLOGIA DE ALIMENTOS
Unidad Ejecutora - UE
artículos
Título:
Functional modulation of Crohn’s disease myofibroblasts by anti-TNF antibodies
Autor/es:
ANTONIO DI SABATINO; SYLVIA L. F. PENDER; CLAIRE L. JACKSON; JOANNA D. PROTHERO; JOHN N. GORDON; LUCIA PICARIELLO; LAURA ROVEDATTI; GUILLERMO DOCENA; GIOVANNI MONTELEONE; DAVID S. RAMPTON; FRANCESCO TONELLI; GINO R. CORAZZA; THOMAS T. MACDONALD
Revista:
GASTROENTEROLOGY
Editorial:
Elsevier
Referencias:
Año: 2006
ISSN:
0016-5085
Resumen:
Background & Aims: Infliximab induces immune cell apoptosis by outside-to-inside signalling through transmembrane tumor necrosis factor (TNF)-a (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-a, and the effects of anti-TNF antibodies on these structural cells have not been studied. We therefore investigated the action of infliximab on apoptosis, production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn’s disease (CD) myofibroblasts. Methods: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analysed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed using in vitro wound-healing scratch assay. Results: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept and p55 TNF receptor-human IgG fusion protein also increased TIMP-1 production. Migration of CD myofibroblasts was significantly enhanced by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti-TIMP-1 neutralising antibody. Infliximab also decreased CD myofibroblast collagen production. Conclusions: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration which may reduce MMP activity, and facilitating the wound healing.