title: Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved.
abstract: The effects of anthocyanidins, the aglycon nucleuses of anthocyanins widely occurring in reddish fruits and vegetables, on the expression of cyclooxygenase-2 (COX-2) were investigated in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. Of five anthocyanidins, delphinidin and cyanidin inhibited LPS-induced COX-2 expression, but pelargonidin, peonidin and malvidin did not. The structure-activity relationship suggest that the ortho-dihydroxyphenyl structure of anthocyanidins on the B-ring appears to be related with the inhibitory actions. Delphinidin, the most potent inhibitor, caused a dose-dependent inhibition of COX-2 expression at both mRNA and protein levels. Western blotting analysis indicated that delphinidin inhibited the degradation of IkappaB-alpha, nuclear translocation of p65 and CCAAT/enhancer-binding protein (C/EBP)delta and phosphorylation of c-Jun, but not CRE-binding protein (CREB). Moreover, delphinidin suppressed the activations of mitogen-activated protein kinase (MAPK) including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase. MAPK inhibitors (U0126 for MEK1/2, SB203580 for p38 kinase and SP600125 for JNK) specifically blocked LPS-induced COX-2 expression. Thus, our results demonstrated that LPS-induced COX-2 expression by activating MAPK pathways and delphinidin suppressed COX-2 by blocking MAPK-mediated pathways with the attendant activation of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1) and C/EBPdelta. These findings provide the first molecular basis that anthocyanidins with ortho-dihydroxyphenyl structure may have anti-inflammatory properties through the inhibition of MAPK-mediated COX-2 expression.
authors.affiliation: Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima City 890-0065, Japan. hou@chem.agri.kagoshima-u.ac.jp
authors.forename: De-Xing
authors.initials: DX
authors.lastname: Hou
authors.forename: Takashi
authors.initials: T
authors.lastname: Yanagita
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Uto
authors.forename: Satoko
authors.initials: S
authors.lastname: Masuzaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujii
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000872:Anthocyanins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; C017185:delphinidin