Abstract:
Inflammatory bowel disease (IBD) is defined as an inflammatory disorder of the gastrointestinal tract of unknown aetiology that presents in distinct clinical manifestations including Crohn’s disease (CD) and ulcerative colitis (UC). Although details concerning the etiology of IBD remain ambiguous, IBD is specifically seen as a representation of abnormal immune responses to microbes in the gut lumen, especially in individuals with a genetic predisposition to develop persistent mucosal inflammation. Among the many factors implicated, activation of the NF-KB pathway is thought to be involved in its pathogenesis in addition to increased production of pro-inflammatory c}tokines by lymphocytes and epithelial cells, suggesting that anti-inflammatory compounds may ameliorate this chronic pathological process. Caffeic acid phenethyl ester (CAPE), a bioactive polyphenol from honeybee propolis, has been shown to have anti-inflammatory and cytoprotective effects in vitro and in vivo. However, this bioactive potential still requires more scientific research that can lead to utilization of CAPE in functional food development. To improve our understanding in the regulatory mechanisms and function of CAPE in disease control, selected in vitro cell culture systems including epithelial (intestinal) and immune cells were used to investigate the structure-activity relationship of CAPE with regard to the down-regulation of inflammatory responses and activation of the oxidative stress elements via NF-KB and Nrfil/Keapl signalling. CAPE significantly inhibited TNF-induced IP-l0 expression in intestinal epithelial cells. Using various analogues, it is demonstrated that substitution of catechol hydroxyl groups and addition of one extra hydroxyl group on ring B reversed the functional activity of CAPE to inhibit IP-10 production. The anti-inflammatory potential of CAPE was confirmed in ileal tissue explants and embryonic fibroblasts derived from T NFAARE’/+ mice. Interestingly, CAPE inhibited both TNF- and LPS-induced IP-10 production in a dose-dependent manner, independent of p38 MAPK, HO-l and Nrf2 signalling pathways. In addition it has been found that CAPE did not inhibit TNF- induced IKB phosphorylation/degradation or nuclear translocation of p65/RelA, but targeted downstream signalling events at the level of transcription factor recruitment to the gene promoter as well as IRFl signalling. Furthermore CAPE protected epithelial cells from oxidative stress through induction of HO-1 via Nrf2 and c-Jun signalling.
