Clostridium difficile toxin A誘発腸炎におけるサイトカインの役割

―IFN-γの生物学的役割より―

抄録

Clostridium difficile (C. difficile) is a major causative agent of antibiotics-associated diarrhea and pseudomembranous colitis in humans. Pathogenic strains of C. difficile release toxin A, which is referred as enterotoxin due to its capacity to disrupt intestinal epithelial structure. Toxin A causes tissue damages directly by glucosylation of Rho and indirectly by inducing massive infiltration of neutrophils. We previously observed that interferon (IFN)-γ-deficient mice exhibited less neutrophil infiltration and tissue damages in several types of acute inflammation in liver. These observations prompted us to explore the roles of IFN-γ in toxin A-induced acute enteritis model. Injection of toxin A into ileal loops caused massive fluid secretion, disruption of epithelial structure, and massive neutrophil infiltration in wild-type (WT) mice, accompanied with increases in IFN-γ mRNA expression and protein contents in the intestine. A double-color immunofluorescence analysis detected IFN-γ protein in infiltrating neutrophils and to a lesser degree, CD3-positive lymphocytes. On the contrary, toxin A failed to induce fluid secretion, disruption of intestinal epithelial structure, and neutrophil infiltration in IFN-γ-deficient mice. Similarly, pretreatment of neutralizing anti-IFN-γ antibody prevented toxin A-induced enteritis. These observations suggest that IFN-γ is a good molecular target for the control of C. difficile-associated pseudomembranous colitis.