title: Suppression of nuclear factor-kappaB activity in macrophages by chylomicron remnants: modulation by the fatty acid composition of the particles.
abstract: Current evidence indicates that chylomicron remnants (CMR) induce macrophage foam cell formation, an early event in atherosclerosis. Inflammation also plays a part in atherogenesis and the transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated. In this study, the influence of CMR on the activity of NF-kappaB in macrophages and its modulation by the fatty acid composition of the particles were investigated using macrophages derived from the human monocyte cell line THP-1 and CMR-like particles (CRLPs). Incubation of THP-1 macrophages with CRLPs caused decreased NF-kappaB activation and downregulated the expression of phospho-p65-NF-kappaB and phospho-IkappaBalpha (pIkappaBalpha). Secretion of the inflammatory cytokines tumour necrosis factor alpha, interleukin-6 and monocyte chemoattractant protein-1, which are under NF-kappaB transcriptional control, was inhibited and mRNA expression for cyclooxygenase-2, an NF-kappaB target gene, was reduced. CRLPs enriched in polyunsaturated fatty acids compared with saturated or monounsaturated fatty acids had a markedly greater inhibitory effect on NF-kappaB binding to DNA and the expression of phospho-p65-NF-kappaB and pIkappaB. Lipid loading of macrophages with CRLPs enriched in polyunsaturated fatty acids compared with monounsaturated fatty acids or saturated fatty acids also increased the subsequent rate of cholesterol efflux, an effect which may be linked to the inhibition of NF-kappaB activity. These findings demonstrate that CMR suppress NF-kappaB activity in macrophages, and that this effect is modulated by their fatty acid composition. This downregulation of inflammatory processes in macrophages may represent a protective effect of CMR which is enhanced by dietary polyunsaturated fatty acids.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, London, UK.
authors.forename: Clara
authors.initials: C
authors.lastname: De Pascale
authors.forename: Valerie
authors.initials: V
authors.lastname: Graham
authors.forename: Robert C
authors.initials: RC
authors.lastname: Fowkes
authors.forename: Caroline P D
authors.initials: CP
authors.lastname: Wheeler-Jones
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Botham
mesh_terms: D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D053298:Chylomicron Remnants / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005227:Fatty Acids / Q000032:analysis / Q000494:pharmacology*; D005395:Fish Oils / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D010938:Plant Oils / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014280:Triglycerides / Q000032:analysis / Q000494:pharmacology
chemical_list: D018925:Chemokines; D053298:Chylomicron Remnants; D016207:Cytokines; D017931:DNA Primers; D005227:Fatty Acids; D005395:Fish Oils; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010938:Plant Oils; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014280:Triglycerides; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C009564:trilinolein