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.
Original language | English |
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Journal | eLife |
Volume | 9 |
DOIs | |
Publication status | Published - 2 Mar 2020 |
Bibliographical note
© 2020, Jarosz-Griffiths et al.Keywords
- 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