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

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)211-223
Number of pages13
JournalMolecular and Cellular Biochemistry
Volume448
Issue number1-2
DOIs
StatePublished - Nov 1 2018

Keywords

  • Apolipoprotein A-I
  • JNK
  • LXR
  • MEK1/2
  • Macrophages
  • PPAR
  • TNFα
  • p38

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