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Cited by 46Liver Diseases and ImmunityPeroxisome Proliferator-Activated ReceptorsDrug Transport and Resistance Mechanisms

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

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Gallucci, Gina M., Alsuwayt, Bader, Auclair, Adam M., Boyer, James L., Assis, David N., Ghonem, Nisanne S.·2022·Inflammation
DOI 10.1007/s10753-022-01713-1PMC PMC10853883
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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.

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Cited by

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Authors
Gallucci, G. M., Alsuwayt, B., Auclair, A. M., Boyer, J. L., Assis, D. N., & Ghonem, N. S.
Affiliations
  • University of Rhode Island (US)
  • Massachusetts College of Pharmacy and Health Sciences (US)
  • Yale University (US)
Corresponding author
Ghonem, Nisanne S.
ORCID
Venue
Inflammation
Publisher
Springer Science and Business Media LLC
Published
2022-07-15
Volume
45
Issue
6
Pages
2570-2581
ISSN
  • 0360-3997 (ISSN-L)
  • 1573-2576
DOI
10.1007/s10753-022-01713-1
PMC
PMC10853883
OpenAlex
W4285591126
Cited by
46
References
2
Citations by year
2026: 8 · 2025: 15 · 2024: 16 · 2023: 7
FWCI
5.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Inflammation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (P20GM103430)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK034989)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
fenofibrate, NF-κB signaling, PPARα, primary biliary cirrhosis, inflammatory cytokines, macrophages, THP-1 cells, lipopolysaccharide-induced inflammation, IκBα, anti-inflammatory mechanism, cholestasis, IL-1β, TNF-α, interleukin-6, interleukin-8, IL-10, ursodeoxycholic acid
MeSH terms
THP-1 Cells, Adult, Anti-Inflammatory Agents, Humans, Lipopolysaccharides, Liver Cirrhosis, Biliary, Macrophages, Fenofibrate, Tumor Necrosis Factor-alpha, Cytokines, Interleukin-8, NF-kappa B, PPAR alpha

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