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 9

Expression of IL1B, SPDEF, and ERN2 mRNAs is associated with MUC5B mRNA in proximal to terminal airway epithelia in CF.

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Expression of IL1B, SPDEF, and ERN2 mRNAs is associated with MUC5B mRNA ...
Expression of MUC5AC, MUC5B, IL1B, IL1A, SPDEF, ERN1, and ERN2 mRNAs was detected by RNA in situ hybridization in non-CF (control) and CF lung subjects. The representative histological sections contain airways ranging from the proximal (bronchial) airways (the regions containing SMG; the airway luminal diameter is around 5 mm) to intermediate (2–4 mm) and distal (1–2 mm), and further to terminal regions (≤200 μm) in each panel. Detection of expression of these genes was performed on the matched sequential sections for each assay. MUC5AC/MUC5B (A) and IL1B/IL1A (B) mRNAs were detected by RNAscope duplex assays. (C) Detection of SPDEF mRNA expression by Basescope assays. (D) ERN1/ERN2 mRNA expression was detected by RNAscope duplex assays. In B, the inserts at bottom left corners show high-power view of the selected areas of airway tissue from both non-CF and CF subjects, and the inserts at the upper right corners show high-power views of the selected area containing the cells trapped in the luminal mucus plugs in CF lung tissue. In A, C, and D, inserts show high-power view of rectangle-selected areas on airway tissues. Micrographs are representative of RNAscope assays performed with n = 4 non-CF and n = 3 CF lungs. Scale bars: 200 μm. Original magnification, ×60 (insets).