카와웰 (Kahweol)과 카페스톨(Cafestol)의 항염증효과

Abstract

Excessive nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) in stimulated inflammatory cells is thought to be a causative factor of cellular injury in cases of inflammation. Inducible cyclooxygenase-2 (COX-2) has been implicated in the processes of inflammation and carcinogenesis. In recent studies, these have been shown that kahweol and cafestol, coffee-specific diterpenes, exhibit chemoprotective effects. In this study, the effects of kahweol and cafestol on the production of NO, the expression of inducible nitric oxide synthase (iNOS) and COX-2 were investigated in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. When kahweol and cafestol were treated with LPS, the NO production induced by LPS was markedly reduced in a dose-dependent manner. Kahweol and cafestol also directly inhibited the activity of iNOS. In addition, kahweol and cafestol suppressed the expression of iNOS protein and iNOS mRNA. Since iNOS transcription has been shown to be under the control of the transcription factor, NF-κB, the effects of kahweol on NF-κB activation were examined. Transient transfection experiments showed that kahweol and cafestol inhibited NF-κB-dependent transcriptional activity. Moreover, electrophoretic mobility shift assay experiments indicated that kahweol blocked the LPS-induced activation of NF-κB. The results of these studies suggest that the suppression of the transcriptional activation of iNOS by kahweol might be mediated through the inhibition of NF-κB activation. Kahweol and cafestol significantly suppressed the LPS-induced production of prostaglandin E2 (PGE2), expression of COX-2 protein as well as the mRNA, and COX-2 promoter activity in a dose-dependent manner. Furthermore, kahweol blocked the LPS-induced activation of NF-κB through the prevention of IκB degradation and the inhibition of IκB kinase activity. In the mouse carrageenan air pouch model of inflammation, kahweol and cafestol significantly suppressed PGE2 production and COX-2 expression in the pouch. Taken together, the results of this study provide evidence that kahweol and cafestol possess the anti-carcinogenesis property or anti-inflammatory potential which constitutes a previously unrecognized biologic activity, and may provide new insights to explain some of the chemopreventive properties observed in mouse macrophage studies and in animal experiments.