Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

Research output: Contribution to journalArticlepeer-review


  • Heledd H Jarosz-Griffiths
  • Thomas Scambler
  • Chi H Wong
  • Samuel Lara-Reyna
  • Jonathan Holbrook
  • And 9 others
  • Fabio Martinon
  • Sinisa Savic
  • Paul Whitaker
  • Christine Etherington
  • Giulia Spoletini
  • Ian Clifton
  • Anil Mehta
  • Michael F McDermott
  • Daniel Peckham

External organisations

  • University of Leeds
  • Leeds Teaching Hospitals NHS Trust
  • University of Dundee


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.

Bibliographic note

© 2020, Jarosz-Griffiths et al.


Original languageEnglish
Publication statusPublished - 2 Mar 2020
Externally publishedYes


  • Adult, Aminophenols/administration & dosage, Aminopyridines/administration & dosage, Benzodioxoles/administration & dosage, Cystic Fibrosis/drug therapy, Cystic Fibrosis Transmembrane Conductance Regulator/drug effects, Cytokines/metabolism, Down-Regulation, Drug Therapy, Combination, Female, Humans, Indoles/administration & dosage, Inflammation/diet therapy, Interleukin-18/blood, Interleukin-1beta/blood, Male, Monocytes/drug effects, Quinolones/administration & dosage, Tumor Necrosis Factor-alpha/blood, Young Adult