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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Dermatologi och venereologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Dermatology and Venereal Diseases (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

Nyckelord

Cell Line

Tumor

Ceramides

biosynthesis

Cytokines

genetics

metabolism

secretion

Fatty Acids

pharmacology

Humans

Interleukin-1beta

genetics

metabolism

secretion

Interleukin-8

genetics

metabolism

secretion

JNK Mitogen-Activated Protein Kinases

metabolism

Lauric Acids

pharmacology

Leukemia

Linoleic Acid

pharmacology

Monocytes

cytology

drug effects

physiology

Myeloid Differentiation Factor 88

genetics

metabolism

Myristic Acid

pharmacology

Palmitic Acid

pharmacology

Palmitoyl Coenzyme A

metabolism

RNA

Messenger

metabolism

RNA

Small Interfering

Stearic Acids

pharmacology

Transcription Factor AP-1

metabolism

Tumor Necrosis Factor-alpha

genetics

metabolism

secretion

p38 Mitogen-Activated Protein Kinases

metabolism

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