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*
Laboratory of Immunology, I Medical Clinic, University of Mainz, Mainz, Germany; and
Gastroenterology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Recent studies have shown that IL-18, a pleiotropic
cytokine that augments IFN-
production, is produced by intestinal
epithelial cells and lamina propria cells from patients with Crohn’s
disease. In this study, we show that IL-18 is strongly expressed by
intestinal epithelial cells in a murine model of Crohn’s disease
induced by transfer of CD62L+CD4+ T cells into
SCID mice. To specifically down-regulate IL-18 expression in this
model, we constructed an E1/E3-deleted adenovirus expressing IL-18
antisense mRNA, denoted Ad-asIL-18, and demonstrated the capacity of
such a vector to down-regulate IL-18 expression in colon-derived DLD-1
cells and RAW264.7 macrophages. Local administration of the Ad-asIL-18
vector to SCID mice with established colitis led to transduction of
epithelial cells and caused a significant suppression of colitis
activity, as assessed by a newly developed endoscopic analysis system
for colitis. Furthermore, treatment with Ad-asIL-18 induced a
significant suppression of histologic colitis activity and caused
suppression of mucosal IFN- production, whereas IFN- production
by spleen T cells was unaffected. Taken together, these data indicate
an important role for IL-18 in the effector phase of a T cell-dependent
murine model of colitis and suggest that strategies targeting IL-18
expression may be used for the treatment of patients with Crohn’s
disease.
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