Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages

• Published in: Atherosclerosis Vol. 202; no. 2; pp. 382 - 393
• Main Authors: Håversen, Liliana, Danielsson, Kristina Norén, Fogelstrand, Linda, Wiklund, Olov
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.02.2009; Elsevier
• Subjects: Atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; biosynthesis; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Cardiovascular system; Cell Line; Cell Line, Tumor; Ceramide; Ceramides; Ceramides - biosynthesis; Cytokines; Cytokines - genetics; Cytokines - metabolism; Cytokines - secretion; cytology; Dermatologi och venereologi; Dermatology and Venereal Diseases; Diabetes; drug effects; Fatty Acids; Fatty Acids - pharmacology; genetics; Humans; Interleukin-1beta; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Interleukin-1beta - secretion; Interleukin-8; Interleukin-8 - genetics; Interleukin-8 - metabolism; Interleukin-8 - secretion; JNK Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases - metabolism; Lauric Acids; Lauric Acids - pharmacology; Leukemia; Linoleic Acid; Linoleic Acid - pharmacology; Macrophages; Medical sciences; Messenger; metabolism; Microbiology in the Medical Area; Mikrobiologi inom det medicinska området; Monocytes; Monocytes - cytology; Monocytes - drug effects; Monocytes - physiology; Myeloid Differentiation Factor 88; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Myristic Acid; Myristic Acid - pharmacology; p38 Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases - metabolism; Palmitate; Palmitic Acid; Palmitic Acid - pharmacology; Palmitoyl Coenzyme A; Palmitoyl Coenzyme A - metabolism; pharmacology; Pharmacology. Drug treatments; physiology; Proinflammatory cytokines; RNA; RNA, Messenger - metabolism; RNA, Small Interfering; secretion; Serine palmitoyltransferase; Small Interfering; Stearate; Stearic Acids; Stearic Acids - pharmacology; Transcription Factor AP-1; Transcription Factor AP-1 - metabolism; Tumor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - secretion; Vasodilator agents. Cerebral vasodilators; Serine palmitoyltransferase; Palmitate; Atherosclerosis; Stearate; Ceramide; Diabetes; Proinflammatory cytokines; Macrophages; Endocrinopathy; Human; Long chain; Diabetes mellitus; Serine; Cytokine; Sphingolipid; Lipids; Cardiovascular disease; Vascular disease; Saturated fatty acid; Aminoacid; Macrophage
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2008.05.033

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-α, IL-8 and IL-1β, and enhanced lipopolysaccharide (LPS)-induced IL-1β 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-α or IL-1β 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.