| First Author | Chen G | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 10 | Pages | 4433-4450 |
| PubMed ID | 31524632 | Mgi Jnum | J:285627 |
| Mgi Id | MGI:6392943 | Doi | 10.1172/JCI125669 |
| Citation | Chen G, et al. (2019) IL-1beta dominates the promucin secretory cytokine profile in cystic fibrosis. J Clin Invest 129(10):4433-4450 |
| abstractText | 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-1beta, with IL-1alpha, dominated the mucin prosecretory activities of supernatants of airway mucopurulent secretions (SAMS). Like SAMS, IL-1beta alone induced MUC5B and MUC5AC protein secretion and mucus hyperconcentration in CF human bronchial epithelial (HBE) cells. Mechanistically, IL-1beta induced the sterile alpha 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-1alpha and IL-1beta 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-1alpha and/or IL-1beta-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. |
