Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 616, Issue -, Pages 1-12Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2017.01.003
Keywords
Autocrine loop; CFTR; Cystic fibrosis; DCFH-DA; c-Src; IL-beta; IL1RN; Mitochondria; Mitochondrial complex I; MitoSOX; NOX; PP2; Reactive oxygen species (ROS)
Categories
Funding
- National Agency for the Promotion of Science and Technology (ANPCYT) [PICT 2012-1278]
- National Research Council for Science and Technology of Argentina (CONICET) [PIP 2012-0685]
- Pontifical Catholic University of Argentina
- CONICET
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Cystic Fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Previously, we found several genes showing a differential expression in CFDE cells (epithelial cells derived from a CF patient). One corresponded to c-Src; its expression and activity was found increased in CFDE cells, acting as a signaling molecule between the CFTR activity and MUC1 overexpression. Here we report that bronchial 1B3-1 cells (CF cells) also showed increased c-Src activity compared to 'CFFR-corrected' S9 cells. In addition, three different Caco-2 cell lines, each stably transfected with a different CFTR-specific shRNAs, displayed increased c-Src activity. The IL-beta receptor antagonist Ill RN reduced the c-Src activity of Caco-2/pRS26 cells (expressing a CFTR-specific shRNA). In addition, increased mitochondria] and cellular ROS levels were detected in Caco-2/pRS26 cells. ROS levels were partially reduced by incubation with PP2 (c-Src inhibitor) or IL1RN, and further reduced by using the NOX1/4 inhibitor GKT137831. Thus, IL-1 beta -> c-Src and IL-1 beta -> NOX signaling pathways appear to be responsible for the production of cellular and mitochondrial ROS in CFTR-KD cells. In conclusion, IL-beta constitutes a new step in the CFTR signaling pathway, located upstream of c-Src, which is stimulated in cells with impaired CFTR activity. (C) 2017 Elsevier Inc. All rights reserved.
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