1. Academic Validation
  2. Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes

Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes

  • Inflamm Res. 2020 Jan;69(1):51-62. doi: 10.1007/s00011-019-01293-1.
Marie Febvre-James 1 Valérie Lecureur 1 Olivier Fardel 2
Affiliations

Affiliations

  • 1 Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, 35000, Rennes, France.
  • 2 Univ Rennes, Inserm, CHU Rennes, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Campus Santé, 2 Avenue du Pr Léon Bernard, 35043, Rennes, France. olivier.fardel@univ-rennes1.fr.
Abstract

Objective and design: To determine whether inflammatory hepatocytes may constitute primary targets for ruxolitinib, a Janus kinase (JAK) inhibitor, its effects towards expression of hepatic acute-phase proteins, especially C-reactive protein (CRP), were assessed.

Materials: Ruxolitinib effects were analysed in primary human hepatocytes and human hepatoma HepaRG cells exposed to various inflammatory stimuli.

Results: Ruxolitinib was found to fully inhibit lipopolysaccharide (LPS)-induced CRP secretion and mRNA expression, at concentrations (IC50 = 12.9 nM) achievable in human blood. It similarly repressed CRP up-regulation due to several Toll-like Receptor agonists or pro-inflammatory cytokines [interleukin (IL) 1β, IL6 and tumour necrosis factor α] and counteracted LPS-mediated induction of serum amyloid A, fibrinogen, haptoglobin and serpin. Ruxolitinib was additionally found to block the activation of the IL6/JAK/signal transducer and activator of transcription (STAT) pathway triggered by LPS and whose inhibition by the neutralizing anti-IL6 receptor antibody tocilizumab prevented CRP induction.

Conclusion: Ruxolitinib can potently repress induction of CRP in inflammatory human hepatocytes, most likely through targeting the IL6/JAK/STAT signalling cascade. Hepatic production of acute-phase proteins during liver inflammation may, therefore, constitute a target for ruxolitinib.

Keywords

C-reactive protein; Hepatic inflammation; Interleukin 6; JAK inhibition; Ruxolitinib.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16379
    99.93%, JAK2/FLT3抑制剂