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FoxO3 might be involved in the inflammatory response of human monocytes to lipopolysaccharide through regulating expression of toll like receptor 4

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Abstract

Objective

Previous studies have found that forkhead box o3 S574 phosphorylation status can regulate inflammation by inducing monocytes/macrophages apoptosis, and whether it directly affects the inflammatory response of monocytes has not been demonstrated. The aim of this study was to investigate the role of forkhead box o3 in inflammatory response of monocytes against lipopolysaccharide.

Methods

THP-1 cells were used to knock down or overexpress forkhead box o3 and its mutants, and then detect the activation of inflammatory cytokines expression and activation of nuclear factor kappa B after lipopolysaccharide treatment.

Results

The present study demonstrated that lipopolysaccharide can up-regulate forkhead box o3 protein expression, especially the non-phosphorylated form at S574, in a post-transcriptional way. Knockdown of forkhead box o3 attenuated lipopolysaccharide mediated nuclear factor kappa B activation and downstream inflammatory cytokines expression. When overexpressing forkhead box o3, only non-phosphorylated S574A forkhead box o3 mutant enhanced lipopolysaccharide induced nuclear factor kappa B activation and inflammatory cytokines expression. Further studies have found that S574A forkhead box o3 may promote toll like receptor 4 expression through binding and accelerating its transcriptional activity from promoter.

Conclusion

There might be a positive feedback loop between lipopolysaccharide and forkhead box o3 in monocytes to promote the lipopolysaccharide mediated inflammatory response.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Not applicable.

Funding

This work was supported by Senior Medical Talents Program of Chongqing for Young and Middle-aged (2019-181) and Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0200).

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Authors and Affiliations

  1. Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, No: 1 Youyi Road, Yuzhong District, Chongqing, 400016, China

    Shujun Zhang

  2. Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China

    Zhuan Li

  3. Department of Internal Medicine and Liver Center, University of Kansas Medical Center, Kansas City, KS, USA

    Steven Weinman

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  1. Shujun Zhang
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  2. Zhuan Li
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Contributions

Conceptualization, SJZ, ZL and SW; methodology, SJZ and ZL; formal analysis, SJZ, ZL and SW; investigation, SJZ and ZL; writing—original draft preparation, SJZ; writing—review and editing, ZL, SW and SJZ. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Shujun Zhang.

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Zhang, S., Li, Z. & Weinman, S. FoxO3 might be involved in the inflammatory response of human monocytes to lipopolysaccharide through regulating expression of toll like receptor 4. Mol Biol Rep 49, 7611–7621 (2022). https://doi.org/10.1007/s11033-022-07576-x

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