1,3-Diphenylpropenone ameliorates TNBS-induced rat colitis through suppression of NF-κB activation and IL-8 induction

• Published in: Chemico-biological interactions 2012-03, Vol.196 (1-2), p.39-49
• Main Authors: Park, Su-Young, Ku, Sae Kwang, Lee, Eung Seok, Kim, Jung-Ae
• Format: Article
• Language: English
• Subjects: adhesion; Angiogenesis; Animals; anti-inflammatory activity; blood serum; Cell Adhesion - drug effects; Cell Adhesion - immunology; Cell Survival - drug effects; Chalcones - pharmacology; chicks; chorioallantoic membrane; colitis; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; colon; drugs; epithelial cells; HT29 Cells; Humans; IBD; IL-8; Immunohistochemistry; inflammation; Inflammation - drug therapy; Inflammation - immunology; interleukin-6; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Interleukin-6 - immunology; interleukin-8; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Interleukin-8 - immunology; myeloperoxidase; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - immunology; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; NF-kappa B - metabolism; NF-κB; pathogenesis; Phenylpropenone; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA - chemistry; RNA - genetics; signal transduction; sulfonic acid; transcription (genetics); transcription factor NF-kappa B; Trinitrobenzenesulfonic Acid; tumor necrosis factor-alpha; U937 Cells; weight loss
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2012.02.002

► Phenylpropenone derivatives inhibit NF-κB transcriptional activity. ► 1,3-Diphenylpropenone (DPhP) suppresses IL-6 and -8 expression and colitis in rats. ► DPhP inhibits IL-8-induced angiogenesis. ► DPhP is a potential dual-acting compound for the treatment of inflammation and abnormal angiogenesis. In the present study, we examined whether newly synthesized phenylpropenone derivatives, by inhibiting NF-κB activity, would inhibit IL-8 expression, inflammation and abnormal angiogenesis, resulting in amelioration of disease conditions. The phenylpropenone derivatives inhibited NF-κB transcriptional activity, which correlated with their suppressive activity against TNF-α-induced adhesion of U937 human monocytic cells to HT-29 human colonic epithelial cells, an in vitro model of IBD. Among the derivatives, 1,3-diphenylpropenone (DPhP) was most efficacious, and it significantly suppressed TNF-α-induced production of IL-8 which is a proinflammatory and proangiogenic cytokine. The anti-inflammatory activity of DPhP was also confirmed in the trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model. DPhP was protective against the TNBS-induced inflammatory responses, which included weight loss, increased myeloperoxidase activity and mucosal damage. In the colon tissue, DPhP inhibited TNBS-induced NF-κB nuclear translocation, IL-8 and TNF-α expressions, and abnormal angiogenesis. In addition, DPhP also suppressed IL-8-induced angiogenesis, which was revealed by an in vivo assay using chick chorioallantoic membrane. Furthermore, the level of IL-6, a pleiotropic cytokine which is implicated in the pathogenesis of IBD and colitis-associated cancer, was suppressed by DPhP in rat colon tissue and serum. In conclusion, the results suggest that DPhP is a potential dual-acting IBD drug candidate targeting both inflammation and abnormal angiogenesis, possibly through the NF-κB and IL-8 signaling pathway.