Nutrient modification of the innate immune response: A novel mechanism by which saturated fatty acids greatly amplify monocyte inflammation

Eric A. Schwartz, Wei Yang Zhang, Sheetal K. Karnik, Sabine Borwege, Vijay R. Anand, Phyllis S. Laine, Yali Su, Peter D. Reaven

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

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 μmol/L SFA in vitro for 16 hours followed by 1 ng/mL lipopolysaccharide demonstrated enhanced IL-6 and IL-8 mRNA and protein expression (≈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-ζ 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-ζ/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.

Original languageEnglish (US)
Pages (from-to)802-808
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Ceramide
  • Mitogen-activated protein kinase
  • Monocytes
  • Protein kinase C
  • Toll-like receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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