IL-1β dominates the promucin secretory cytokine profile in cystic fibrosis
Gang Chen, … , Wanda K. O’Neal, Richard C. Boucher
Gang Chen, … , Wanda K. O’Neal, Richard C. Boucher
Published September 16, 2019
Citation Information: J Clin Invest. 2019;129(10):4433-4450. https://doi.org/10.1172/JCI125669.
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Research Article Pulmonology

IL-1β dominates the promucin secretory cytokine profile in cystic fibrosis

Abstract

Cystic fibrosis (CF) lung disease is characterized by early and persistent mucus accumulation and neutrophilic inflammation in the distal airways. Identification of the factors in CF mucopurulent secretions that perpetuate CF mucoinflammation may provide strategies for novel CF pharmacotherapies. We show that IL-1β, with IL-1α, dominated the mucin prosecretory activities of supernatants of airway mucopurulent secretions (SAMS). Like SAMS, IL-1β alone induced MUC5B and MUC5AC protein secretion and mucus hyperconcentration in CF human bronchial epithelial (HBE) cells. Mechanistically, IL-1β induced the sterile α motif–pointed domain containing ETS transcription factor (SPDEF) and downstream endoplasmic reticulum to nucleus signaling 2 (ERN2) to upregulate mucin gene expression. Increased mRNA levels of IL1B, SPDEF, and ERN2 were associated with increased MUC5B and MUC5AC expression in the distal airways of excised CF lungs. Administration of an IL-1 receptor antagonist (IL-1Ra) blocked SAMS-induced expression of mucins and proinflammatory mediators in CF HBE cells. In conclusion, IL-1α and IL-1β are upstream components of a signaling pathway, including IL-1R1 and downstream SPDEF and ERN2, that generate a positive feedback cycle capable of producing persistent mucus hyperconcentration and IL-1α and/or IL-1β–mediated neutrophilic inflammation in the absence of infection in CF airways. Targeting this pathway therapeutically may ameliorate mucus obstruction and inflammation-induced structural damage in young CF children.

Authors

Gang Chen, Ling Sun, Takafumi Kato, Kenichi Okuda, Mary B. Martino, Aiman Abzhanova, Jennifer M. Lin, Rodney C. Gilmore, Bethany D. Batson, Yvonne K. O’Neal, Allison S. Volmer, Hong Dang, Yangmei Deng, Scott H. Randell, Brian Button, Alessandra Livraghi-Butrico, Mehmet Kesimer, Carla M.P. Ribeiro, Wanda K. O’Neal, Richard C. Boucher

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Figure 10

Quantification of MUC5B/MUC5AC and IL1B/IL1A mRNA expression in the distal airways of control and CF lungs.

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Quantification of MUC5B/MUC5AC and IL1B/IL1A mRNA expression in the dist...
(A) Quantification of the MUC5B/MUC5AC mRNA signals in superficial epithelia lining of the distal airways (including all the airways with luminal diameter of 1.5 mm or less, regardless of staining status; shown in Figure 9) was determined by morphometric analysis of staining volume density. Quantification of the IL1B/IL1A mRNA signal content present in the luminal areas (B) and signal volume density in the epithelial layers (C) of the distal airways (same criteria as in A) was performed by morphometric analyses. Signal volume density in A and C was normalized to the unit surface area of the basement membrane (BM), while the luminal contents of IL1B/IL1A staining in B was normalized to the unit luminal volume (LV). Measurements of n = 4 control subjects and n = 3 CF subjects were performed. Individual subjects are distinguished by color-matched dots (A–C). Each color dot represents measurement from 1 airway, and the numbers of the airways used in analyses from 1 subject were annotated as n = following the color dots in the figure annotations. Of note, the scatter dots/bar graphs represent cube root–transformed values. The differences of means between the 2 groups (denoted by P values) were analyzed by linear mixed-effects model with subject identification number as random intercept variable. (D) mRNA expression of SPDEF, ERN2, MUC5B, and MUC5AC was quantitatively measured by TaqMan assays (normalized to endogenous GAPDH mRNA) from the airway epithelial cells freshly isolated (passage 0) from nonsmoker, non-CF donors (control, n = 30 codes) and CF donors (n = 24 codes). One code means the cells obtained from 1 individual donor lung. Scatter plots present data as mean ± SEM, and data were analyzed with 2-tailed unpaired Mann-Whitney U test.