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Activation of liver X receptor α protects amyloid β1–40 induced inflammatory and senescent responses in human retinal pigment epithelial cells

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Abstract

Objective

To investigate whether activation of the liver X receptors (LXRs) inhibits amyloid β1–40 (Aβ1–40) induced inflammatory and senescent responses in human retinal pigment epithelial (RPE) cells.

Materials and methods

Confluent cultures of human primary RPE and ARPE-19 cells pretreated with 5 μΜ of TO901317 (TO90), a synthetic agonist of LXR, or vehicle were incubated with 1 μΜ of Aβ1–40 or Aβ40–1. The optimum concentrations of Aβ1–40 and TO90 were determined by cell viability assay. Pro-inflammatory cytokines IL-6, IL-8, MCP-1 were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Expression and localization of an aging protein p16INK4a (p16) were analyzed by western blotting and immunofluorescence. Expressions of LXRs and one of their target genes ATP-binding cassette transporter A1 (ABCA1) were examined by real-time PCR and western blotting. Phosphorylated transcription inhibition factor-κB-α (p-IκB-α) was assessed by western blotting.

Results

A negative linear relationship between the Aβ1–40 concentration and the cell viability was evident, indicating Aβ1–40 decreased ARPE-19 cell viability in a dose-dependent manner. Aβ1–40 enhanced the expression of IL-6, IL-8, MCP-1 as well as p16 in both RPE cell lines at both mRNA and protein levels, whereas TO90 counteracted the detrimental effects. TO90 upregulated the expression of LXRα and its target gene ABCA1, but it did not affect the expression of LXRβ. Meanwhile, TO90 inhibited the phosphorylation of IκB-α mediated by Aβ1–40 stimulation.

Conclusion

Activation of the LXRα-ABCA1 axis may alleviate Aβ1–40 induced inflammatory and senescent responses in RPE cells. The beneficial effect appears associated with the inhibition of the NF-κB signaling pathway.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China Grants (81271033, 81470621), Chongqing Science and Technology Commission (2014pt-sy10002), National Key Clinical Specialties Construction Program of China and a key project of Chongqing Health Bureau (2012-1-026).

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Authors and Affiliations

  1. Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China

    Bingling Dai, Chunyan Lei, Ru Lin, Lifei Tao, Yue Bin, Hui Peng & Bo Lei

  2. Henan Provincial People’s Hospital, Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China

    Bo Lei

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  1. Bingling Dai
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  2. Chunyan Lei
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Correspondence to Hui Peng or Bo Lei.

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Responsible Editor: Graham R. Wallace.

H. Peng and B. Lei contributed equally to the work.

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Dai, B., Lei, C., Lin, R. et al. Activation of liver X receptor α protects amyloid β1–40 induced inflammatory and senescent responses in human retinal pigment epithelial cells. Inflamm. Res. 66, 523–534 (2017). https://doi.org/10.1007/s00011-017-1036-4

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  • DOI: https://doi.org/10.1007/s00011-017-1036-4

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