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Direct effect of infliximab on intestinal mucosa sustains mucosal healing: exploring new mechanisms of action

Digestive and Liver Disease, In Press, Accepted Manuscript, Available online 19 December 2015, Available online 19 December 2015

Abstract

Background

Infliximab is effective in inflammatory bowel disease through several mechanisms, possibly acting at the mucosal level.

Aim

To assess the role of infliximab on intestinal mucosa and whether it contributes to mucosal healing.

Methods

Human colonic mucosal biopsies were incubated with or without infliximab. Cultured biopsies were evaluated for histological staining, CD68, CD3, E-cadherin and phospho-extracellular signal-regulated kinases (ERK) expression, and apoptosis. A scratch assay and MTT assay were performed with CaCo2 cells in the presence of infliximab and/or tumour necrosis factor (TNF)-α or treated with supernatants obtained from human peripheral blood mononuclear cells or human intestinal fibroblasts treated with TNF-α and infliximab alone or in association.

Results

infliximab-treated biopsies displayed a better histological appearance, reduced inflammation with an increase of E-cadherin, phospho-ERK and apoptosis. Supernatants showed lower TNF-α, IL-17, IL-6 and IL-8 concentration, with an increase in fibroblast-growth-factor. Motility at scratch assay and proliferation at MTT assay of Caco2 cells displayed differential modulation by TNF-α and infliximab, directly or through supernatants of human intestinal fibroblasts and human peripheral blood mononuclear cells exposed to them.

Conclusion

infliximab contributes to the mucosal healing process by acting directly at an intestinal mucosal level; infliximab indirectly affects epithelial cell migration and proliferation by acting on both fibroblasts and leukocytes.

Keywords: Infliximab, TNF-α, mucosal healing, wound repair, cellular proliferation.

Footnotes

a Internal Medicine Department, Gastroenterology Division, Catholic University of Sacred Heart, Rome, Italy

b Institute of Pathology, Catholic University of Sacred Heart, Rome, Italy

c Institute of Hygiene, Catholic University of Sacred Heart, Rome, Italy

d Surgery Department, Catholic University of Sacred Heart, Rome, Italy

Corresponding author. Università Cattolica del Sacro Cuore, “A. Gemelli” Hospital, Largo A. Gemelli 8, 00168, Rome, Italy Tel.Fax: +39 06 3015 5923

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