@article{c8acd793a50c42b49cf06dec0c180654,
title = "Klotho Inhibits Interleukin-8 Secretion from Cystic Fibrosis Airway Epithelia",
abstract = "Chronic inflammation is a hallmark of cystic fibrosis (CF) and associated with increased production of transforming growth factor (TGF) β and interleukin (IL)-8. α-klotho (KL), a transmembrane or soluble protein, functions as a co-receptor for Fibroblast Growth Factor (FGF) 23, a known pro-inflammatory, prognostic marker in chronic kidney disease. KL is downregulated in airways from COPD patients. We hypothesized that both KL and FGF23 signaling modulate TGF β-induced IL-8 secretion in CF bronchial epithelia. Thus, FGF23 and soluble KL levels were measured in plasma from 48 CF patients and in primary CF bronchial epithelial cells (CF-HBEC). CF patients showed increased FGF23 plasma levels, but KL levels were not different. In CF-HBEC, TGF-β increased KL secretion and upregulated FGF receptor (FGFR) 1. Despite increases in KL, TGF-β also increased IL-8 secretion via activation of FGFR1 and Smad 3 signaling. However, KL excess via overexpression or supplementation decreased IL-8 secretion by inhibiting Smad 3 phosphorylation. Here, we identify a novel signaling pathway contributing to IL-8 secretion in the CF bronchial epithelium with KL functioning as an endocrine and local anti-inflammatory mediator that antagonizes pro-inflammatory actions of FGF23 and TGF-β.",
author = "Stefanie Krick and Nathalie Baumlin and Aller, {Sheyla Paredes} and Carolina Aguiar and Alexander Grabner and Juliette Sailland and Eliana Mendes and Andreas Schmid and Lixin Qi and David, {Nicolae V.} and Patrick Geraghty and Gwendalyn King and Birket, {Susan E.} and Rowe, {Steven M.} and Christian Faul and Matthias Salathe",
note = "Funding Information: The authors thank John Stephen Dennis for technical assistance and the staff at the CF centers in West Palm Beach and the University of Miami for helping to collect the CF blood samples. The authors also thank Heather Hathorne, Tonya Meadows, Steve Duncan and Melissa Pflueger for their help to obtain IRB approval and access to the BAL specimen from the UAB Biorepository and Dawn Duncan and Scott Blumhof for helping to prepare lysates and cDNA from kl+/+ and kl−/− tissues. This work was supported by the Flight Attendant Medical Research Institute (YFAC152003; to S.K.) and the Cystic Fibrosis Foundation (CFF KRICK1610; to S. K. and SALATH14G0 to M.S.), the James & Esther King Florida Biomedical Research Program (5JK02 to M.S.), the American Heart Association (A.G., C.F.), the American Diabetes Association (C.F.), grant R01HL128714 (C.F.) from the National Institutes of Health and the UAB CF Center P30 Award (DK072482) from the National Institutes of Health. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41598-017-14811-0",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}