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eLife

eLife

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Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

Published:2 March 2020 DOI: 10.7554/eLife.54556 PMID: 32118580
Heledd H Jarosz-Griffiths, Thomas Scambler, Chi H Wong, Samuel Lara-Reyna, Jonathan Holbrook, Fabio Martinon, Sinisa Savic, Paul Whitaker, Christine Etherington, Giulia Spoletini, Ian Clifton, Anil Mehta, Michael F McDermott, Daniel Peckham

Abstract

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Tezacaftor 1152311-62-0 C26H27F3N2O6 204 suppliers $9.00-$1600.00
Tezacaftor 1152311-62-0 C26H27F3N2O6 204 suppliers $9.00-$1600.00
Tezacaftor 1152311-62-0 C26H27F3N2O6 204 suppliers $9.00-$1600.00
Tezacaftor 1152311-62-0 C26H27F3N2O6 204 suppliers $9.00-$1600.00

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