TNF-α Induces a Pro-Inflammatory Phenotypic Shift in Monocytes through ACSL1: Relevance to Metabolic Inflammation

Fatema Al-Rashed, Zunair Ahmad, Mina Amin Iskandar, Jaakko Tuomilehto, Fahd Al-Mulla, Rasheed Ahmad

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

BACKGROUND/AIMS: TNF-α-mediated pro-inflammatory phenotypic change in monocytes is known to be implicated in the pathogenesis of metabolic inflammation and insulin resistance. However, the mechanism by which TNF-α-induces inflammatory phenotypic shift in monocytes is poorly understood. Since long-chain acyl-CoA synthetase 1 (ACSL1) is associated with inflammatory monocytes/macrophages, we investigated the role of ACSL1 in the TNF-α-driven inflammatory phenotypic shift in the monocytes. METHODS: Monocytes (Human monocytic THP-1 cells) were stimulated with TNF-α. Inflammatory phenotypic markers (CD16, CD11b, CD11c and HLA-DR) expression was determined with real time RTPCR and flow cytometry. IL-1β and MCP-1 were determined by ELISA. Signaling pathways were identified by using ACSL1 inhibitor, ACSL1 siRNA and NF-κB reporter monocytic cells. Phosphorylation of NF-κB was analyzed by western blotting and flow cytometry. RESULTS: Our data show that TNF-α induced significant increase in the expression of CD16, CD11b, CD11c and HLA-DR. Inhibition of ACSL1 activity in the cells with triacsin C significantly suppressed the expression of these inflammatory markers. Using ACSL-1 siRNA, we further demonstrate that TNF-α-induced inflammatory markers expression in monocytic cells requires ACSL1. In addition, IL-1b and MCP-1 production by TNF-α activated monocytic cells was significantly blocked by the inhibition of ACSL-1 activity. Interestingly, elevated NF-κB activity resulting from TNF-α stimulation was attenuated in ACSL1 deficient cells. CONCLUSION: Our findings provide an evidence that TNF-α-associated inflammatory polarization in monocytes is an ACSL1 dependent process, which indicates its central role in TNF-α-driven metabolic inflammation.

Original languageEnglish
Pages (from-to)397-407
Number of pages11
JournalCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Volume52
Issue number3
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Cell Line
  • Chemokine CCL2/analysis
  • Coenzyme A Ligases/antagonists & inhibitors
  • Gene Expression Regulation/drug effects
  • HLA-DR Antigens/genetics
  • Humans
  • Inflammation/metabolism
  • Interleukin-1beta/analysis
  • Monocytes/cytology
  • NF-kappa B/metabolism
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering/metabolism
  • Receptors, IgG/genetics
  • Triazenes/chemistry
  • Tumor Necrosis Factor-alpha/pharmacology

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