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The Second-Generation mTOR Kinase Inhibitor INK128 Exhibits Anti-inflammatory Activity in Lipopolysaccharide-Activated RAW 264.7 Cells

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Abstract

Cross-talk between the mTOR (mechanistic target of rapamycin) and NF-κB (nuclear factor kappa-B) pathways has been reported to regulate macrophage responses to lipopolysaccharide (LPS). In this study, we aimed to explore the effect of INK128, a second-generation inhibitor of mTOR, on the inflammatory cytokine production in LPS-stimulated RAW 264.7 cells. Our data showed that INK128 strikingly inhibited the phosphorylation of p70S6K, 4E-BP1 and AKTSer473 in both unstimulated and LPS-stimulated cells. Although it increased the phosphorylation levels of inhibitor kappa-B (IκB) in LPS-stimulated cells, INK128 did not significantly change the levels of NF-κB phosphorylation. In addition, LPS-induced expression of IL-1β and IL-6 was markedly suppressed by INK128 at both mRNA and protein levels. However, the expression of Tumor necrosis factor-alpha (TNF-α protein), but not its mRNA level, was suppressed by this reagent. Our results suggest that the mTOR inhibitor INK128 not only regulates the NF-κB signaling but also influences the inflammatory cytokine expression at both transcriptional and translational levels.

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Acknowledgments

This work is supported by grants from the National Natural Science Foundation of China (No. 81373423, 81173604), the Specialized Research Program of "Twelfth Five-Year Plan" of China (No. 2011ZX09307-303-03) and the Fundamental Research Funds for the Central Universities (No. 21612411).

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632, China

    Hao Pan, Dong-Yun Ouyang, Yao Wang, Xiao-Feng Hou & Xian-Hui He

  2. Department of Cell Biology, Jinan University, Guangzhou, 510632, China

    Li-Hui Xu

  3. Department of Fetal Medicine, the First Affiliated Hospital of Jinan University, Guangzhou, 510632, China

    Qing-Bin Zha

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  1. Hao Pan
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Correspondence to Dong-Yun Ouyang or Xian-Hui He.

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Pan, H., Xu, LH., Ouyang, DY. et al. The Second-Generation mTOR Kinase Inhibitor INK128 Exhibits Anti-inflammatory Activity in Lipopolysaccharide-Activated RAW 264.7 Cells. Inflammation 37, 756–765 (2014). https://doi.org/10.1007/s10753-013-9794-9

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