Interleukin 8 Secretion from Monocytes of Subjects Heterozygous for the ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutation Is Altered

ABSTRACT Patients with cystic fibrosis (CF) exhibit an excessive host inflammatory response. The aim of this study was to determine (i) whether interleukin 8 (IL-8) secretion is increased from monocytes from subjects heterozygous as well as homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and (ii) whether this is due to increased cell surface lipopolysaccharide (LPS) receptors or, alternatively, increased activation of mitogen-activated protein kinases (MAPK). The basal level of IL-8 secretion was higher from monocytes from CF patients than from monocytes from healthy controls (P = 0.02) and obligate heterozygotes (parents of the CF patients). The 50% effective concentrations for LPS-induced IL-8 production for monocytes from both CF patients and obligate heterozygotes were 100-fold lower than those for monocytes from healthy controls (P < 0.05). No differences in the levels of IL-1β production were seen between these groups. Expression of the LPS surface receptors CD14 and Toll-like receptor 4 were not different between CF patients and healthy controls. In contrast, phosphorylation of the MAPKs p38 and ERK occurred at lower doses of LPS in monocytes from patients heterozygous and homozygous for CFTR mutations. These results indicate that a single allelic CFTR mutation is sufficient to augment IL-8 secretion in response to LPS. This is not a result of increased LPS receptor expression but, rather, is associated with alterations in MAPK signaling.

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Increased NaCl-induced interleukin-8 production by human bronchial epithelial cells is enhanced by the ΔF508/W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene

Cytokine ◽

10.1016/j.cyto.2006.03.003 ◽

2006 ◽

Vol 33 (6) ◽

pp. 309-316 ◽

Cited By ~ 11

Author(s):

M CHAN ◽

K CHMURA ◽

E CHAN

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Bronchial Epithelial Cells ◽

Interleukin 8 ◽

Transmembrane Conductance Regulator ◽

Regulator Gene ◽

Human Bronchial Epithelial Cells ◽

Transmembrane Conductance ◽

Bronchial Epithelial ◽

Cystic Fibrosis Transmembrane

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Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment

Scientific Reports ◽

10.1038/s41598-021-99184-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ciaran A. Shaughnessy ◽

Pamela L. Zeitlin ◽

Preston E. Bratcher

Keyword(s):

Cystic Fibrosis ◽

Early Death ◽

New Combination ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Acute And Chronic Treatment ◽

Cftr Mutations ◽

Small Molecule Modulators ◽

Cystic Fibrosis Transmembrane

AbstractCystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.

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Diagnosis of cystic fibrosis in adulthood and eligibility for novel CFTR modulator therapy

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2020-139278 ◽

2021 ◽

pp. postgradmedj-2020-139278

Author(s):

Hannah Farley ◽

Sarah Poole ◽

Stephen Chapman ◽

William Flight

Keyword(s):

Cystic Fibrosis ◽

Chronic Respiratory Disease ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Radiological Data ◽

Patient Database ◽

Cftr Mutations ◽

History Of ◽

Autosomal Recessive Condition ◽

Cystic Fibrosis Transmembrane

BackgroundCystic fibrosis (CF) is an autosomal recessive condition that primarily manifests as a chronic respiratory disease. CF is usually diagnosed in early childhood or through newborn screening although in a small but important group, diagnosis is not made until adulthood. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are now available for most genetic causes of CF highlighting the importance of identifying people with late presentations of CF.AimWe aimed to identify the clinical characteristics of people diagnosed with CF in adulthood and their resulting eligibility for novel CFTR modulator therapies.DesignRetrospective single-centre cohort study.MethodsPatients diagnosed with CF at age 18 years or older were identified from a patient database. Paper and electronic medical records were reviewed and clinical, microbiological and radiological data at diagnosis were recorded.ResultsNineteen patients were identified. Median age at diagnosis was 38 years (range: 19–71) and 9 (47%) were female. All patients had a history of chronic respiratory symptoms and 18/19 (94%) had radiological evidence of bronchiectasis. All patients had two pathogenic CFTR mutations identified with 16/19 (84%) compound heterozygotes for the F508del mutation. The majority of patients had a CFTR genotype considered eligible for CFTR modulator therapy (84% and 89% according to European and US licences, respectively).ConclusionsAdult patients with unexplained chronic bronchiectasis should be thoroughly investigated for CF. A low index of suspicion will help to identify adults with undiagnosed CF who are likely to benefit from CFTR modulator therapy.

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