Nutrient Modification of the Innate Immune Response A Novel Mechanism by Which Saturated Fatty Acids Greatly Amplify Monocyte Inflammation

作者：Schwartz Eric A^*; Zhang Wei Yang; Karnik Sheetal K; Borwege Sabine; Anand Vijay R; Laine Phyllis S; Su Yali; Reaven Peter D

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2010, 30(4): 802-U372.

DOI：10.1161/ATVBAHA.109.201681

• ceramide
• mitogen-activated protein kinase
• monocytes
• protein kinase C
• Toll-like receptor

Objective-Monocyte/macrophage inflammation is an important contributor to diabetes and cardiovascular disease. Studies have suggested saturated fatty acids (SFA) induce monocyte inflammation in a Toll-like receptor-4-dependent manner, but recent data suggest SFA do not directly interact with Toll-like receptor-4. The present study tests the novel hypothesis that metabolism of SFA cooperatively amplifies Toll-like receptor-4-mediated inflammation.
Methods and Results-THP-1 monocytes exposed to 100 mu mol/L SFA in vitro for 16 hours followed by 1 ng/mL lipopolysaccharide demonstrated enhanced IL-6 and IL-8 mRNA and protein expression (approximate to 3-fold higher than the sum of individual responses to SFA and lipopolysaccharide). SFA had similar effects on THP-1 macrophages and primary human monocytes. This amplified lipopolysaccharide response could be blocked by inhibition of SFA metabolism to ceramide and restored by cell-permeable ceramide. Both SFA and ceramide activated PKC-zeta and the mitogen-activated protein kinases Erk, JNK, and p38. Inhibition of these pathways prevented the SFA-induced increase in cytokine expression.
Conclusion-These results provide evidence for potent amplification of monocyte/macrophage innate immune responses by a novel pathway requiring metabolism of SFA to ceramide and activation of PKC-zeta/mitogen-activated protein kinases. These findings demonstrate how nutrient excess may modulate innate immune system activation and possibly contribute to development of diabetes and cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2010; 30: 802-808.)

• 出版日期2010-4