期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-14811-0
关键词
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资金
- Flight Attendant Medical Research Institute [YFAC152003]
- Cystic Fibrosis Foundation [CFF KRICK1610, SALATH14G0]
- James & Esther King Florida Biomedical Research Program [5JK02]
- American Heart Association
- American Diabetes Association
- National Institutes of Health [R01HL128714]
- UAB CF Center P30 Award from the National Institutes of Health [DK072482]
Chronic inflammation is a hallmark of cystic fibrosis (CF) and associated with increased production of transforming growth factor (TGF) beta and interleukin (IL)-8. alpha-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 beta-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-beta increased KL secretion and upregulated FGF receptor (FGFR) 1. Despite increases in KL, TGF-beta 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 antiinflammatory mediator that antagonizes pro-inflammatory actions of FGF23 and TGF-beta.
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