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

Abstract

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.

Molecular characterization and expression profiles in response to bacterial infection of Chinese soft-shelled turtle interleukin-8 (IL-8), the first reptilian chemokine gene

“…GenBank accession numbers for these sequences used are listed in Table 2. avian IL-8. In mammals, the ELR motif was known to be responsible for promoting angiogenesis, one of the most important abilities of this group of chemokines [25][26][27]. Chicken IL-8 possessed an ELR motif and was shown to involve in receptor binding in human or chicken IL-8 [4,28].…”

“…NF-kB is a major transcription factor that regulates genes responsible for both the innate and the adaptive immune response. It has been reported that activation of NF-kB and its dependent genes may be one of the important pathways used by IL-8 during inflammation angiogenesis [27]. c-Rel, a number of NFkB family and predominantly expressed in immune cells, could regulate gene transcription in T cells and was implicated in leukocyte trafficking, particularly that related to Th1-mediated inflammation [36].…”

Apple Flavonoid Phloretin Inhibits Escherichia coli O157:H7 Biofilm Formation and Ameliorates Colon Inflammation in Rats

“…The method used to establish the model of TNBS-induced rat colitis was adapted from that described previously (46). Sprague-Dawley rats (age, 7 to 8 weeks) were purchased from Samtaco bio Korea (Osan, South Korea).…”

Acute phase response in Chinese soft-shelled turtle (Trionyx sinensis) with Aeromonas hydrophila infection

“…It contains a 1265 bp promoter region, in which several putative binding sites for TATA box, NF-B, C/EBP ␤, c-Rel (3 sites), oct-1, ARP-1 (2 sites), HLF and HSF are present, suggesting that the transcription of turtle SAA may be regulated by multiple transcription factors in inflammatory response. Among these factors, NF-B is a major transcription factor that regulates the genes responsible for both the innate and the adaptive immune response (Thapa et al, 2008); c-Rel, a member of NF-B family, is predominantly expressed in immune cells. It regulates gene transcription in T cells and is implicated in leukocyte trafficking, is particularly related to Th1-mediated inflammation (Bunting et al, 2007).…”