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.