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Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis.

Authors
  • Gallucci, Gina M1
  • Alsuwayt, Bader2
  • Auclair, Adam M1
  • Boyer, James L3
  • Assis, David N3
  • Ghonem, Nisanne S4
  • 1 College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA.
  • 2 School of Pharmacy, Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA.
  • 3 Yale School of Medicine, Liver Center, New Haven, CT, USA.
  • 4 College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA. [email protected].
Type
Published Article
Journal
Inflammation
Publisher
Springer-Verlag
Publication Date
Dec 01, 2022
Volume
45
Issue
6
Pages
2570–2581
Identifiers
DOI: 10.1007/s10753-022-01713-1
PMID: 35838934
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Chronic liver diseases, e.g., cholestasis, are negatively impacted by inflammation, which further aggravates liver injury. Pharmacotherapy targeting the peroxisome proliferator-activated receptor alpha (PPARα), e.g., fenofibrate, has recently become an off-label therapeutic option for patients with refractory cholestasis. Clinical studies show that fibrates can reduce some pro-inflammatory cytokines in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); however, its anti-inflammatory mechanisms have not been established. Numerous cytokines are regulated by the transcription factor nuclear receptor kappa B (NF-κB), and PPARα has been shown to interfere with NF-κB signaling. This study investigates the anti-inflammatory mechanism of fenofibrate by inhibiting NF-κB signaling in human macrophages and clinical outcomes in patients with PBC. For adult patients with PBC and an incomplete biochemical response to ursodiol (13-15 mg/kg/day), the addition of fenofibrate (145-160 mg/day) reduced serum levels of TNF-α, IL-17A, IL-1β, IL-6, IL-8, and MCP-1 and increased IL-10. In THP-1 cells, pretreatment with fenofibrate (125 μM) reduced LPS-stimulated peak concentrations of IL-1β (- 63%), TNF-α (- 88%), and IL-8 (- 54%), in a PPARα-dependent manner. Treatment with fenofibrate prior to LPS significantly decreased nuclear NF-κB p50 and p65 subunit binding by 49% and 31%, respectively. Additionally, fenofibrate decreased nuclear NF-κB p50 and p65 protein expression by 66% and 55% and increased cytoplasmic levels by 53% and 54% versus LPS alone, respectively. Lastly, fenofibrate increased IκBα levels by 2.7-fold (p < 0.001) vs. LPS. These data demonstrate that fenofibrate reduces pro-inflammatory cytokines section by inhibiting in NF-κB signaling, which likely contribute to its anti-inflammatory effects during chronic liver diseases. © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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