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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Clotrimazole Ameliorates Intestinal Inflammation and Abnormal Angiogenesis by Inhibiting Interleukin-8 Expression through a Nuclear Factor-B-Dependent Manner

College of Pharmacy, Yeungnam University, Gyeongsan, South Korea (D.T., J.S.L., S.-Y.P., J.B.K., K.-J.K., M.-K.K., H.G.C., J.-A.K.); School of Medicine, Pusan National University, Pusan, South Korea (Y.-H.B., S.-K.B.); and Research Center, Samil Pharmaceutical Co. Ltd., Ansan, South Korea (Y.-J.P.)

Increased interleukin (IL)-8 plays an important role not only in activation and recruitment of neutrophils but also in inducing exaggerated angiogenesis at the inflamed site. In the present study, we investigated the fact that clotrimazole (CLT) inhibits intestinal inflammation, and the inhibitory action is mediated through suppression of IL-8 expression. In the trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model, CLT dose-dependently protected from the TNBS-induced weight loss, colon ulceration, and myeloperoxidase activity increase. In the lesion site, CLT also suppressed the TNBS-induced angiogenesis, IL-8 expression, and nuclear factor (NF)-B activation. In a cellular model of colitis using tumor necrosis factor (TNF)--stimulated HT29 colon epithelial cells, treatment with CLT significantly suppressed TNF--mediated IL-8 induction and NF-B transcriptional activity revealed by a luciferase reporter gene assay. Furthermore, cotreatment with CLT and pyrrolidine dithiocarbamate, a NF-B inhibitor, synergistically reduced the NF-B transcriptional activity as well as IL-8 expression. In an in vitro angiogenesis assay, CLT suppressed IL-8-induced proliferation, tube formation, and invasion of human umbilical vein endothelial cells. The in vivo angiogenesis assay using chick chorioallantoic membrane also showed that CLT significantly inhibited the IL-8-induced formation of new blood vessels. Taken together, these results suggest that CLT may prevent the progression of intestinal inflammation by not only down-regulating IL-8 expression but also inhibiting the action of IL-8 in both colon epithelial and vascular endothelial cells during pathogenesis of intestinal inflammation.

Address correspondence to: Dr. Jung-Ae Kim, College of Pharmacy, Yeungnam University, 214-1 Dae-Dong, Yeungnam University, Gyeongsan 712-749, Korea. E-mail: jakim{at}yu.ac.kr