Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 118, Issue 8, Pages 2131-2140Publisher
WILEY
DOI: 10.1002/jcb.25850
Keywords
CFTR; CFTR SIGNALING; INTRACELLULAR CHLORIDE; CYSTIC FIBROSIS; INFLAMMATION
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Funding
- National Agency for the Promotion of Science and Technology (ANPCYT) [PICT 2007-00628, PICT 2012-1278]
- National Scientific and Technical Research Council (CONICET) [PIP 11220080102551 2009-2011, PIP 11220110100685 2012-2014]
- Pontifical Catholic University of Argentina (UCA)
- Fundacion Pablo Cassara
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Cystic fibrosis (CF) is caused by mutations in the CFTR gene, which encodes a cAMP-regulated chloride channel. Several cellular functions are altered in CF cells. However, it is not clear how the CFTR failure induces those alterations. We have found previously several genes differentially expressed in CF cells, including c-Src, MUC1, MTND4, and CISD1 (CFTR-dependent genes). Recently, we also reported the existence of several chloride-dependent genes, among them GLRX5 and RPS27. Here, varying the intracellular chloride concentration [Cl-](i) of IB3-1 CF bronchial epithelial cells, we show that IL-1 mRNA expression and secretion are also under Cl- modulation. The response to Cl- is biphasic, with maximal effects at 75mM Cl-. The regulation of the IL-1 mRNA expression involves an IL-1 autocrine effect, since in the presence of the IL-1 receptor antagonist IL1RN or anti-IL-1 blocking antibody, the mRNA response to Cl- disappeared. Similar effects were obtained with the JNK inhibitor SP600125, the c-Src inhibitor PP2 and the IKK inhibitor III (BMS-345541). On the other hand, the IL-1 secretion is still modulated by Cl- in the presence of IL-1RN, IL-1 blocking antibody, or cycloheximide, suggesting that Cl- is affecting the IL-1 maturation/secretion, which in turn starts an autocrine positive feedback loop. In conclusion, the Cl- anion acts as a second messenger for CFTR, modulating the IL-1 maturation/secretion. The results also imply that, depending on its intracellular concentration, Cl- could be a pro-inflammatory mediator. J. Cell. Biochem. 118: 2131-2140, 2017. (c) 2016 Wiley Periodicals, Inc.
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