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Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor activity

¹ Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, 13288 Marseille Cedex 9, France
² Institut National de la Santé et de la Recherche Médicale (INSERM) U631, 13288 Marseille Cedex 9, France
³ Centre National de la Recherche Scientifique (CNRS) UMR6102, 13288 Marseille Cedex 9, France
⁴ Service d'Anatomie Pathologique, Faculté de Médecine Nord, 13915 Marseille Cedex 9, France
⁵ Etablissement Français du Sang Alpes Méditerranée, 13005 Marseille Cedex 9, France

CORRESPONDENCE Franck Galland: fgpn{at}ciml.univ-mrs.fr

Colitis involves immune cell–mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR) antagonist. We further demonstrate that Vanin-1, by antagonizing PPAR, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/pantetheinase activity might be a new target for therapeutic intervention in inflammatory bowel disease.

Abbreviations used: ATRA, all trans-retinoic acid; BADGE, bisphenol A diglycidyl ether; COX, cyclooxygenase; 15-d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; GSH, glutathione; IBD, inflammatory bowel disease; IEC, intestinal epithelial cell; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; PPAR, peroxisome proliferator-activated receptor; SCID, severe combined immunodeficient; TNBS, 2,4,6-trinitrobenzene sulfonic acid.

C. Berruyer's present address is National de la Santé et de la Recherche Médicale, U599 27, 13009 Marseille, France.

F.M. Martin's present address is The Scripps Research Institute, Department of Molecular and Experimental Medicine, MEM-131, La Jolla, CA 92037.

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