Journal article
Inflammatory cytokines TNF-alpha and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators
The Journal of clinical investigation, Vol.131(16), e150398
08/16/2021
DOI: 10.1172/JCI150398
PMCID: PMC8363270
PMID: 34166230
Abstract
Without cystic fibrosis transmembrane conductance regulator-mediated (CFTR-mediated) HCO3- secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this time course matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNF-alpha and IL-17 (TNF-alpha+IL-17), 2 inflammatory cytokines that are elevated in CF airways. TNF-alpha+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl- /HCO3- exchanger. Moreover, when CF epithelia were exposed to TNF-alpha+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted bythese results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator-induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3- secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that, for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cell-autonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.
Details
- Title: Subtitle
- Inflammatory cytokines TNF-alpha and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators
- Creators
- Tayyab Rehman - Roy J. and Lucille A. Carver College of MedicinePhilip H. Karp - University of IowaPing Tan - Roy J. and Lucille A. Carver College of MedicineBrian J. Goodell - Roy J. and Lucille A. Carver College of MedicineAlejandro A. Pezzulo - Roy J. and Lucille A. Carver College of MedicineAndrew L. Thurman - Roy J. and Lucille A. Carver College of MedicineIan M. Thornell - Roy J. and Lucille A. Carver College of MedicineSamantha L. Durfey - University of WashingtonMichael E. Duffey - University at Buffalo, State University of New YorkDavid A. Stoltz - Roy J. and Lucille A. Carver College of MedicineEdward F. McKone - University College DublinPradeep K. Singh - University of WashingtonMichael J. Welsh - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.131(16), e150398
- DOI
- 10.1172/JCI150398
- PMID
- 34166230
- PMCID
- PMC8363270
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 12
- Grant note
- Gilead Sciences Research Scholars Program in Cystic Fibro-sis CFF RDP pilot grant Cys-tic Fibrosis Foundation Research Development Program (CFF RDP) (University of Iowa and University of Washington) HL140261; HL136813; HL091842; HL051670 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Vertex Investigator-Initiated Studies Program; Vertex Pharmaceuticals
- Language
- English
- Date published
- 08/16/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9984259444702771
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