title: Omega-3 docosahexaenoic acid and procyanidins inhibit cyclo-oxygenase activity and attenuate NF-κB activation through a p105/p50 regulatory mechanism in macrophage inflammation.
abstract: The inflammatory response has been implicated in the pathogenesis of many chronic diseases. Along these lines, the modulation of inflammation by consuming bioactive food compounds, such as ω-3 fatty acids or procyanidins, is a powerful tool to promote good health. In the present study, the administration of DHA (docosahexaenoic acid) and B1, B2 and C1 procyanidins, alone or in combination, prevented the inflammatory response induced by the LPS (lipopolysaccharide) endotoxin in human macrophages and brought them to the homoeostatic state. DHA and B1 were strong and selective negative regulators of cyclo-oxygenase 1 activity, with IC50 values of 13.5 μM and 8.0 μM respectively. Additionally, B2 and C1 were selective inhibitors of pro-inflammatory cyclo-oxygenase 2 activity, with IC50 values of 9.7 μM and 3.3 μM respectively. Moreover, DHA and procyanidins prevented the activation of the NF-κB (nuclear factor κB) cascade at both early and late stages with shared mechanisms. These included inhibiting IκBα (inhibitor of NF-κB α) phosphorylation, inducing the cytoplasmic retention of pro-inflammatory NF-κB proteins through p105 (NF-κB1) overexpression, favouring the nuclear translocation of the p50-p50 transcriptional repressor homodimer instead of the p50-p65 pro-inflammatory heterodimer, inhibiting binding of NF-κB DNA to κB sites and, finally, decreasing the release of NF-κB-regulated cytokines and prostaglandins. In conclusion, DHA and procyanidins are strong and selective inhibitors of cyclo-oxygenase activity and NF-κB activation through a p105/p50-dependent regulatory mechanism.
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Martinez-Micaelo
authors.forename: Noemi
authors.initials: N
authors.lastname: González-Abuín
authors.forename: Ximena
authors.initials: X
authors.lastname: Terra
authors.forename: Cristobal
authors.initials: C
authors.lastname: Richart
authors.forename: Anna
authors.initials: A
authors.lastname: Ardèvol
authors.forename: Monserrat
authors.initials: M
authors.lastname: Pinent
authors.forename: Mayte
authors.initials: M
authors.lastname: Blay
mesh_terms: D044946:Biflavonoids / Q000494:pharmacology; D002392:Catechin / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D044945:Proanthocyanidins / Q000378:metabolism* / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D044946:Biflavonoids; D016861:Cyclooxygenase Inhibitors; D015525:Fatty Acids, Omega-3; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; D044945:Proanthocyanidins; D051996:Transcription Factor RelA; C479579:procyanidin B1; D000072000:NF-KappaB Inhibitor alpha; D004281:Docosahexaenoic Acids; C479580:procyanidin B2; D002392:Catechin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone