Anti-inflammatory effect of lovastatin is mediated via the modulation of NF-κB and inhibition of HDAC1 and the PI3K/Akt/mTOR pathway in RAW264.7 macrophages

Choi,Hyung-Wook; Shin,Pyung-Gyun; Lee,Ji-Hyun; Choi,Woo-Suk; Kang,Min-Jae; Kong,Won-Sik; Oh,Min-Ji; Seo,Yong-Bae; Kim,Gun-Do

doi:10.3892/ijmm.2017.3309

Anti-inflammatory effect of lovastatin is mediated via the modulation of NF-κB and inhibition of HDAC1 and the PI3K/Akt/mTOR pathway in RAW264.7 macrophages

Authors:
- Hyung-Wook Choi
- Pyung-Gyun Shin
- Ji-Hyun Lee
- Woo-Suk Choi
- Min-Jae Kang
- Won-Sik Kong
- Min-Ji Oh
- Yong-Bae Seo
- Gun-Do Kim
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Affiliations: Department of Microbiology, Pukyong National University, Busan 48513, Republic of Korea, Mushroom Research Division, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong 27709, Republic of Korea, Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
Published online on: December 5, 2017 https://doi.org/10.3892/ijmm.2017.3309
Pages: 1103-1109

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Abstract

Lovastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor that is clinically used for the prevention of cardiovascular diseases. Although it has been reported that lovastatin has anti-inflammatory properties in several studies, how lovastatin regulates the inflammation is still unclear. To evaluate the effect of lovastatin on nitric oxide production (NO) in RAW264.7 macrophages, NO production assay was performed. Also, cell viability was measured to confirm cytotoxicity. Level of tumor necrosis factor-α (TNF-α) transcription was measured by reverse transcription polymerase chain reaction (RT-PCR) from total RNA in RAW264.7 cells. Western blot analysis and immunofluorescence staining were used to investigate the regulation of lovastatin on the expression, phosphorylation, and nuclear translocation of cellular proteins. The results of the present study revealed that lovastatin reduced nitric oxide production via the reduction of inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. The mRNA level of TNF-α was reduced in presence of lovastatin. In addition, lovastatin downregulated histone deacetylase 1 (HDAC1), resulting in the accumulation of acetylated histone H3 and heat shock protein 70. Furthermore, the expression of phosphoinositide 3-kinase catalytic subunits α and β was reduced under lovastatin treatment, and the phosphorylation of Akt and mammalian target of rapamycin was consequently inhibited. Lovastatin also inhibited the phosphorylation of inhibitor of nuclear factor (NF)-κBα and the translocation of NF-κB into the nucleus. Therefore, the present study demonstrates that lovastatin inhibits the expression of pro-inflammatory mediators, including iNOS and TNF-α, through the suppression of HDAC1 expression, PI3K/Akt phosphorylation and NF-κB translocation in LPS-stimulated RAW264.7 macrophage cells.

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