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Tumor necrosis factor α stimulates endogenous apolipoprotein A-I expression and secretion by human monocytes and macrophages: role of MAP-kinases, NF-κB, and nuclear receptors PPARα and LXRs

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Abstract

Apolipoprotein A-I (ApoA-I) is the main structural and functional protein component of high-density lipoprotein. ApoA-I has been shown to regulate lipid metabolism and inflammation in macrophages. Recently, we found the moderate expression of endogenous apoA-I in human monocytes and macrophages and showed that pro-inflammatory cytokine tumor necrosis factor α (TNFα) increases apoA-I mRNA and stimulates ApoA-I protein secretion by human monocytes and macrophages. Here, we present data about molecular mechanisms responsible for the TNFα-mediated activation of apoA-I gene in human monocytes and macrophages. This activation depends on JNK and MEK1/2 signaling pathways in human monocytes, whereas inhibition of NFκB, JNK, or p38 blocks an increase of apoA-I gene expression in the macrophages treated with TNFα. Nuclear receptor PPARα is a ligand-dependent regulator of apoA-I gene, whereas LXRs stimulate apoA-I mRNA transcription and ApoA-I protein synthesis and secretion by macrophages. Treatment of human macrophages with PPARα or LXR synthetic ligands as well as knock-down of LXRα, and LXRβ by siRNAs interfered with the TNFα-mediated activation of apoA-I gene in human monocytes and macrophages. At the same time, TNFα differently regulated the levels of PPARα, LXRα, and LXRβ binding to the apoA-I gene promoter in THP-1 cells. Obtained results suggest a novel tissue-specific mechanism of the TNFα-mediated regulation of apoA-I gene in monocytes and macrophages and show that endogenous ApoA-I might be positively regulated in macrophage during inflammation.

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Acknowledgements

We thank Prof. A. D. Denisenko (Institute of Experimental Medicine, Russia) for helpful discussions and reviewing the manuscript.

Funding

The work has been supported by the Russian Science Foundation (Grant No 17-15-01326).

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Author notes

  1. Denis A. Mogilenko

    Present address: Université de Lille, Inserm, Institut Pasteur de Lille, U1011-EGID, 59000, Lille, France

  2. Vladimir S. Shavva and Denis A. Mogilenko equally contributed to the work.

Authors and Affiliations

  1. Department of Biochemistry, Institute of Experimental Medicine, acad. Pavlov St., 12, Saint Petersburg, Russia, 197376

    Vladimir S. Shavva, Denis A. Mogilenko, Ekaterina V. Nekrasova, Ekaterina E. Larionova, Anna V. Babina, Ella B. Dizhe, Boris V. Missyul & Sergey V. Orlov

  2. Department of Embryology, St. Petersburg State University, Saint Petersburg, Russia

    Vladimir S. Shavva, Denis A. Mogilenko & Sergey V. Orlov

  3. Department of Immunology, Institute of Experimental Medicine, Saint Petersburg, Russia

    Andrey S. Trulioff & Igor V. Kudriavtsev

  4. Department of Cytology and Histology, St. Petersburg State University, Saint Petersburg, Russia

    Igor V. Kudriavtsev & Ekaterina E. Larionova

  5. Pavlov First St. Petersburg State Medical University, Saint Petersburg, Russia

    Anna V. Babina

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  1. Vladimir S. Shavva
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Shavva, V.S., Mogilenko, D.A., Nekrasova, E.V. et al. Tumor necrosis factor α stimulates endogenous apolipoprotein A-I expression and secretion by human monocytes and macrophages: role of MAP-kinases, NF-κB, and nuclear receptors PPARα and LXRs. Mol Cell Biochem 448, 211–223 (2018). https://doi.org/10.1007/s11010-018-3327-7

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