CLOSTRIDIUM-DIFFICILE TOXIN-A STIMULATES MACROPHAGE-INFLAMMATORY PROTEIN-2 PRODUCTION IN RAT INTESTINAL EPITHELIAL-CELLS

Neutrophil infiltration of the colonic mucosa is a hallmark of Clostri dium difficile toxin A-mediated enterocolitis. Macrophage-inflammatory protein-2 (MIP-2) is a potent neutrophil chemoattractant secreted by rat macrophages and epithelial cells in response to inflammatory stimu li. In this work, we report that administration of toxin A into rat il eal loops increased mucosal levels of MIP-2 before the onset of fluid secretion and mucosal neutrophil infiltration. Administration of rabbi t anti-MIP-2 IgG, but not control IgG, reduced toxin A-mediated secret ion (by 58%), mucosal permeability (by 80%), and myeloperoxidase activ ity (by 85%). Immunohistochemical analysis demonstrated increased MIP- 2 expression in intestinal epithelial and lamina propria cells 1 h aft er toxin A administration. Intestinal epithelial cells purified from t oxin A-exposed ileal loops also showed increased MIP-2 mRNA expression and MIP-2 protein release that was inhibited by pretreatment of rats with the transcriptional inhibitor actinomycin D, These results indica te that C, difficile toxin A induces MIP-2 release from intestinal epi thelial cells and that MIP-2 contributes to neutrophil mucosal influx during toxin A enteritis.