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.

Alpha‐Klotho, a critical protein for lung health, is not expressed in normal lung

“…Gao et al performed IHC and IB with commercial antibodies reporting intense αKlotho staining in the lungs of healthy nonsmokers compared to markedly reduced staining in smokers and COPD patients, whereas αKlotho staining intensity was similar in ozone‐exposed mice compared to air‐exposed controls. Also using commercial anti‐αKlotho antibodies, αKlotho staining was detected by IHC and IB in bronchial epithelium of cystic fibrosis patients. However, in that study the two detected bands (~65 and ~80 kD) were below the expected size of full‐length/secreted αKlotho (~130 kD) and no control IHC was shown.…”

“…Also using commercial anti‐αKlotho antibodies, αKlotho staining was detected by IHC and IB in bronchial epithelium of cystic fibrosis patients. However, in that study the two detected bands (~65 and ~80 kD) were below the expected size of full‐length/secreted αKlotho (~130 kD) and no control IHC was shown. Furthermore, the detected bands are inconsistent with the single band (130 kD) shown in another study by the same group using the same antibody that probed airway epithelia from COPD patients .…”

Fibroblast growth factor 23 and Klotho contribute to airway inflammation

“…5b, right panel). When compared to their wild type litter mates, bronchoalveolar lavage fluid (BALF) from kl −/− mice contained more cells, specifically neutrophils (23) and macrophages/monocytes (Fig. 5c).…”

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

“…Further renal conditions including fibrosis , albuminuria and autosomal dominant polycystic kidney disease (ADPKD) are associated with elevated FGF23 levels. Also, impaired liver function and lung disease stimulate FGF23 production. Patients with heart failure or atherosclerosis have higher FGF23 levels.…”

“…Transforming growth factor β (TGFβ) stimulates Fgf23 gene expression by up‐regulating SOCE . Increased production of TGFβ in cystic fibrosis stimulates FGF23 signalling via upregulation of FGFR1 leading to interleukin IL‐8 secretion . In addition, an inhibitory effect of TGFβ on FGF23 promoter activity may also be relevant .…”