Cell adhesion molecules play a pivotal role in chronic inflammation and pathological angiogenesis. In the present study, we investigated the inhibitory effects of clotrimazole (CLT) on tumor necrosis factor (TNF)-alpha-induced changes in adhesion molecule expression. CLT dose-dependently inhibited monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expressions in TNF-alpha-stimulated HT29 colonic epithelial cells. This inhibitory action of CLT correlated with a significant reduction in TNF-alpha-induced adhesion of monocytes to HT29 cells, which was comparable to the inhibitory effects of anti-ICAM-1 and VCAM-1 monoclonal antibodies on monocyte-epithelial adhesion. These inhibitory actions of CLT were, at least in part, attributable to the inhibition of redox sensitive NF-kappaB activation, as CLT inhibited TNF-alpha-induced ROS generation as well as NF-kappaB nuclear translocation and activation in HT29 cells. Furthermore, the inhibition of TNF-alpha-induced monocyte adhesion was also mimicked by the specific NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). Inflammatory mediators including TNF-alpha have known to promote angiogenesis, which in turn further contributes to inflammatory pathology. Therefore, we additionally evaluated whether CLT modulates TNF-alpha-induced angiogenesis using in vivo chick chorioallantoic membrane (CAM) assay. The CAM assay showed that CLT dose-dependently attenuated TNF-alpha-induced angiogenesis, and the effect was correlated with decreased inflammation of the CAM tissue. In conclusion, our results suggest that CLT can inhibit TNF-alpha-triggered expression of adhesion molecules, ICAM-1 and VCAM-1, and angiogenesis during inflammation.

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In inflammatory bowel disease (IBD), colon epithelial cells increased the expression of a variety of inflammatory mediators, cell adhesion molecules and chemokines. In this study, we examined the effect of novel propenone derivatives, 1,3‐diphenyl‐propenone (DPhP), 3‐phenyl‐1‐thiophen‐2‐yl‐propenone (PhT2P), 3‐phenyl‐1‐thiophen‐3‐yl‐propenone (PhT3P) and 1‐furan‐2‐yl‐3‐phenyl‐propenone (FPhP), on inflammatory cytokine‐induced responses in HT‐29 human colon epithelial cells. We found that DPhP most effectively blocked TNF‐α‐induced adhesion of U937 monocytes to HT‐29 cells, which is an initial step of colon inflammation. DPhP inhibited the expression of IL‐8, MCP‐1 and ICAM‐1 in a concentration‐dependent manner. When HT‐29 cells were transfected with NF‐κB‐Luc plasmid, DPhP significantly inhibited TNF‐α‐induced luciferase activity. In trinitrobenzene sulfonic acid (TNBS)‐induced rat colitis model, DPhP dose‐dependently protected from the TNBS‐induced weight loss, myeloperoxidase activity increase. At the same time, DPhP suppressed the TNBS‐induced mRNA expression of IL‐8, IL‐6 and MCP‐1. Taken together, the results suggest that DPhP may be a potential candidate to suppress the colon inflammation via inhibition of major pro‐inflammatory cytokines involved in intestinal inflammation.