IL-1β dominates the promucin secretory cytokine profile in cystic fibrosis
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
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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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 4

IL-1β, but not IL-13, increases mucus percentage of solids in the apical secretions of CF HBE cells.

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IL-1β, but not IL-13, increases mucus percentage of solids in the apical...
Fully differentiated non-CF and CF HBE cells were exposed to control (PBS), IL-1β, or IL-13 (10 ng/ml from basolateral side in media) for 1 week. (A) Apical secretions from non-CF and CF HBE cells were collected by washing the apical surface of HBE cells with PBS containing 10 mM DL-dithiothreitol (DTT) to remove mucus. Secreted MUC5B and MUC5AC proteins were identified by mucin agarose gel Western blot. HBE cells from n = 5 non-CF donors and n = 5 CF donors were used for each treatment condition. (B) MUC5B and MUC5AC protein content shown in A was semiquantified with Licor Odyssey software. Scatter plots represent mean ± SD. Data were analyzed with 1-way ANOVA followed by Dunnett’s test. (C) The percentage of mucus solids content, an index of hydration of apical secretions, was measured from HBE cells after 1 week of treatment with control, IL-1β (cells from n = 9 non-CF and n = 9 CF donors), or IL-13 (cells from n = 5 non-CF and n = 5 CF donors). Data were analyzed with 1-way ANOVA followed by Dunnett’s test.