Marie Febvre-James1, Valérie Lecureur1, Olivier Fardel2. 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.
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 humanhepatomaHepaRG 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.
Entities:
Keywords:
C-reactive protein; Hepatic inflammation; Interleukin 6; JAK inhibition; Ruxolitinib
Authors: Leonard Daniël Samson; Peter Engelfriet; W M Monique Verschuren; H Susan J Picavet; José A Ferreira; Mary-Lène de Zeeuw-Brouwer; Anne-Marie Buisman; A Mieke H Boots Journal: Immun Ageing Date: 2022-01-17 Impact factor: 6.400
Authors: Melinda J Gooderham; Giampiero Girolomoni; Julian O Moore; Jonathan I Silverberg; Robert Bissonnette; Seth Forman; Elena Peeva; Pinaki Biswas; Hernan Valdez; Gary Chan Journal: Dermatol Ther (Heidelb) Date: 2022-08-07