Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages.
Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activation of macrophages, and thus the development of atherosclerosis. In this study, we investigated the effect of the saturated fatty acids (SFA) palmitate, stearate, myristate and laurate, and the unsaturated fatty acid linoleate, on the production of proinflammatory cytokines in phorbol ester-differentiated THP-1 cells, a model of human macrophages. Palmitate induced secretion and mRNA expression of TNF-alpha, IL-8 and IL-1 beta, and enhanced lipopolysaccharide (LPS)-induced IL-1 beta secretion. Proinflammatory cytokine secretion was also induced by stearate, but not by the shorter chain SFA, myristate and laurate, or linoleate. Triacsin C abolished the palmitate-induced cytokine secretion, suggesting that palmitate activation to palmitoyl-CoA is required for its effect. Palmitate-induced cytokine secretion was decreased by knockdown of serine palmitoyltransferase and mimicked by C(2)-ceramide, indicating that ceramide is involved in palmitate-induced cytokine secretion. Palmitate phosphorylated p38 and JNK kinases, and blocking of these kinases with specific inhibitors diminished the palmitate-induced cytokine secretion. Palmitate also activated the AP-1 (c-Jun) transcription factor. Knockdown of MyD88 reduced the palmitate-induced IL-8, but not TNF-alpha or IL-1 beta secretion. In conclusion, our data suggest that the long-chain SFA induce proinflammatory cytokines in human macrophages via pathways involving de novo ceramide synthesis. This might contribute to the activation of macrophages in atherosclerotic plaques, especially in type 2 diabetes.
Håversen
Liliana
L
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Bruna Stråket 16, 41345 Göteborg, Sweden. liliana.haversen@wlab.gu.se
Danielsson
Kristina Norén
KN
Fogelstrand
Linda
L
Wiklund
Olov
O
D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007850:Lauric Acids / Q000494:pharmacology; D007938:Leukemia; D019787:Linoleic Acid / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D019814:Myristic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D013229:Stearic Acids / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002518:Ceramides; D016207:Cytokines; D005227:Fatty Acids; D053583:Interleukin-1beta; D016209:Interleukin-8; D007850:Lauric Acids; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013229:Stearic Acids; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019814:Myristic Acid; C030358:lauric acid; D010171:Palmitoyl Coenzyme A; D019308:Palmitic Acid; C031183:stearic acid; D019787:Linoleic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases