CFTR failure produces a Cl- accumulation that induces epiregulin upregulation through an IL1B loop

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It was a great pleasure to do this work with Macarena, a former graduate student and now a posdoctoral student in my lab. Further work is now in progress to determine the physiological relevance of the EGFR activation in cells with impaired CFTR activity. The accumulation of Cl- is responsible for initiation of the IL-1b loop and the vicious negative feedback loop of IL-1b. This may have consequences in many diseases in which fibrosis and oxidative stress are involved through IL-1b, not only cystic fibrosis, including neurodegenerative diseases, heart fibrosis, etc. Further readings: 1: Massip-Copiz MM, Santa-Coloma TA. Extracellular pH and lung infections in cystic fibrosis. Eur J Cell Biol. 2018 Aug;97(6):402-410. doi: 10.1016/j.ejcb.2018.06.001. Epub 2018 Jun 18. Review. PubMed PMID: 29933921. 2: Valdivieso ÁG, Dugour AV, Sotomayor V, Clauzure M, Figueroa JM, Santa-Coloma TA. N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells. Redox Biol. 2018 Jun;16:294-302. doi: 10.1016/j.redox.2018.03.006. Epub 2018 Mar 14. PubMed PMID: 29573703; PubMed Central PMCID: PMC5953002. 3: Massip-Copiz M, Clauzure M, Valdivieso ÁG, Santa-Coloma TA. Epiregulin (EREG) is upregulated through an IL-1β autocrine loop in Caco-2 epithelial cells with reduced CFTR function. J Cell Biochem. 2018 Mar;119(3):2911-2922. doi: 10.1002/jcb.26483. Epub 2017 Nov 24. PubMed PMID: 29091309. 4: Valdivieso ÁG, Mori C, Clauzure M, Massip-Copiz M, Santa-Coloma TA. CFTR modulates RPS27 gene expression using chloride anion as signaling effector. Arch Biochem Biophys. 2017 Nov 1;633:103-109. doi: 10.1016/j.abb.2017.09.014. Epub 2017 Sep 21. PubMed PMID: 28941802. 5: Massip-Copiz MM, Clauzure M, Valdivieso ÁG, Santa-Coloma TA. CFTR impairment upregulates c-Src activity through IL-1β autocrine signaling. Arch Biochem Biophys. 2017 Feb 15;616:1-12. doi: 10.1016/j.abb.2017.01.003. Epub 2017 Jan 11. PubMed PMID: 28088327. 6: Clauzure M, Valdivieso ÁG, Massip-Copiz MM, Mori C, Dugour AV, Figueroa JM, Santa-Coloma TA. Intracellular Chloride Concentration Changes Modulate IL-1β Expression and Secretion in Human Bronchial Epithelial Cultured Cells. J Cell Biochem. 2017 Aug;118(8):2131-2140. doi: 10.1002/jcb.25850. Epub 2017 Apr 18. PubMed PMID: 27996167. 7: Massip Copiz MM, Santa Coloma TA. c- Src and its role in cystic fibrosis. Eur J Cell Biol. 2016 Oct;95(10):401-413. doi: 10.1016/j.ejcb.2016.08.001. Epub 2016 Aug 11. Review. PubMed PMID: 27530912. 8: Valdivieso ÁG, Clauzure M, Massip-Copiz M, Santa-Coloma TA. The Chloride Anion Acts as a Second Messenger in Mammalian Cells - Modifying the Expression of Specific Genes. Cell Physiol Biochem. 2016;38(1):49-64. doi: 10.1159/000438608. Epub 2016 Jan 8. PubMed PMID: 26741366. 9: Clauzure M, Valdivieso AG, Massip Copiz MM, Schulman G, Teiber ML, Santa-Coloma TA. Disruption of interleukin-1β autocrine signaling rescues complex I activity and improves ROS levels in immortalized epithelial cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One. 2014 Jun 5;9(6):e99257. doi: 10.1371/journal.pone.0099257. eCollection 2014. PubMed PMID: 24901709; PubMed Central PMCID: PMC4047112. 10: Valdivieso AG, Santa-Coloma TA. CFTR activity and mitochondrial function. Redox Biol. 2013 Feb 5;1:190-202. doi: 10.1016/j.redox.2012.11.007. Review. PubMed PMID: 24024153; PubMed Central PMCID: PMC3757715. 11: Valdivieso AG, Clauzure M, Marín MC, Taminelli GL, Massip Copiz MM, Sánchez F, Schulman G, Teiber ML, Santa-Coloma TA. The mitochondrial complex I activity is reduced in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One. 2012;7(11):e48059. doi: 10.1371/journal.pone.0048059. Epub 2012 Nov 21. PubMed PMID: 23185247; PubMed Central PMCID: PMC3504030. 12: Valdivieso ÁG, Marín MC, Clauzure M, Santa-Coloma TA. Measurement of cystic fibrosis transmembrane conductance regulator activity using fluorescence spectrophotometry. Anal Biochem. 2011 Nov 15;418(2):231-7. doi: 10.1016/j.ab.2011.07.029. Epub 2011 Jul 30. PubMed PMID: 21864494. 13: Taminelli GL, Sotomayor V, Valdivieso AG, Teiber ML, Marín MC, Santa-Coloma TA. CISD1 codifies a mitochondrial protein upregulated by the CFTR channel. Biochem Biophys Res Commun. 2008 Jan 25;365(4):856-62. Epub 2007 Nov 29. PubMed PMID: 18047834. 14: Valdivieso AG, Marcucci F, Taminelli G, Guerrico AG, Alvarez S, Teiber ML, Dankert MA, Santa-Coloma TA. The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis. Biochem Biophys Res Commun. 2007 May 11;356(3):805-9. Epub 2007 Mar 19. PubMed PMID: 17382898.

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