1733-P: Cross Talk between Palmitate and LPS Leads to a Synergistic IL-6 Production in Human Monocytic Cells: Implications for Metabolic Inflammation

IL-6 concentrations are positively correlated with the level of obesity and associated proinflammatory state that promotes the development of insulin resistance. The metabolic stimuli that regulate IL-6 production has not been fully revealed. Since metabolic concentrations of plasma LPS and palmitate (free fatty acid) are increased in obesity and are considered as potent inducers of IL-6. Therefore, we have examined whether interaction of palmitate with LPS trigger the production of IL-6 in human monocytic cells. THP-1 and primary human monocytic cells incubated with palmitate and LPS together produced more biological active IL-6 compared to monocytes incubated with palmitate or LPS alone. Synergistic IL-6 induction was blocked either by silencing the expression of TLR4 or MyD88. However, IRF3 did not have impact on this synergism. Non-metabolizable analog as well as specific metabolic pathway inhibitors of palmitate showed that esterification of palmitate with coenzyme A (CoA) involved, in part, in this synergism. Furthermore, synergistic upregulation of IL-6 was suppressed by histone acetyltransferase inhibitor (anacardic acid). Histone deacetylase (HDAC) inhibitor (sodium butyrate) enhanced IL-6 production.

In conclusion, our results show that an interaction between palmitate and LPS depends on TLR4/MyD88, lipid metabolism and epigenetic signaling pathways, which leads to the elevation of IL-6, providing interesting pathophysiological connections among FFAs, LPS, and IL-6 in settings such as obesity or metabolic inflammation.