Inhibitory effect of the gut microbial linoleic acid metabolites on BV-2 microglial cell activation

[Speaker] Shiori Ikeguchi:1
[Co-author] Yasuhiko Izumi:1,2, Shigenobu Kishino:3, Jun Ogawa:3, Akinori Akaike:1, Toshiaki Kume:1,4
1:Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan, 2:Department of Pharmacology, Kobe Pharmaceutical University, Japan, 3:Department of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan, 4:Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan

Background: Microglial activation is related to the pathogenesis of neurodegenerative diseases. Therefore, the inhibition of microglial activation may be a promising therapeutic strategy for progressive neurodegenerative diseases. Long-chain fatty acids, such as DHA and EPA, are known to have anti-inflammatory effects in the brain. 10-oxo-trans-11-octadecenoic acid (KetoC) and 10-hydroxy-cis-12-octadecenoic acid (HYA) are long-chain fatty acids generated from linoleic acid by the gut lactic acid bacterium Lactobacillus plantarum. These fatty acids have been reported to have anti-inflammatory activity in the intestine. However, little is known about their effects in the brain. In this study, we investigated the effects of KetoC and HYA on lipopolysaccharide (LPS)-induced inflammatory processes in mouse microglial cells.

Methods: BV-2 mouse microglial cells were cultured with DMEM medium supplemented with 10% FBS. Production of nitric oxide (NO) was measured by the Griess method. Western blotting was performed to detect the expression level of the proteins such as inducible nitric oxide synthase (iNOS), phosphorylated Mitogen-activated protein kinase (p-MAPK). The receptor expression was confirmed by RT-PCR.

Results: In BV-2 cells, KetoC and HYA inhibited LPS-induced NO production and suppressed the expression of iNOS. It has been reported that long-chain fatty acids are peroxisome proliferator-activated receptor (PPAR) and the G-protein coupled receptor 120 (GPR120) ligands. Next, we investigated the involvement of PPAR and GPR120 in the inhibitory effects of KetoC and HYA. However, GPR120 and PPAR antagonists did not affect the inhibitory action of both fatty acids. We then investigated the effect of both fatty acids on LPS-induced nuclear transport of nuclear factor-kappa B (NF-kB), IkB degradation and the phosphorylation of MAPK. KetoC and HYA had no effect on LPS-induced nuclear transport of NF-kB and IkB degradation. Similarly, no effect on p38 or JNK phosphorylation was observed. However, KetoC and HYA were found to inhibit ERK phosphorylation induced by LPS.

Conclusions: These results suggest that KetoC and HYA suppress LPS-induced NO production and iNOS expression in microglia, and this anti-inflammatory mechanism may be exerted through the inhibition of ERK phosphorylation.
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