Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function

CFTR is a cAMP-regulated chloride channel, whose mutations produce cystic fibrosis. The impairment of CFTR activity increases the intracellular Cl- concentration, which in turn produces an increased interleukin-1β (IL-1β) secretion. The secreted IL-1β then induces an autocrine positive feedback loop...

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Autores: Massip Copiz, María Macarena, Clauzure, Mariangeles, Valdivieso, Ángel Gabriel, Santa Coloma, Tomás Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/48628
Acceso en línea:http://hdl.handle.net/11336/48628
Access Level:acceso abierto
Palabra clave:Cftr
Cystic-Fibrosis
Epiregulin-Ereg
Il-1beta
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
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oai_identifier_str oai:ri.conicet.gov.ar:11336/48628
network_acronym_str AR
network_name_str Argentina
spelling Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function Massip Copiz, María Macarena Clauzure, Mariangeles Valdivieso, Ángel Gabriel Santa Coloma, Tomás Antonio Cftr Cystic-Fibrosis Epiregulin-Ereg Il-1beta https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 CFTR is a cAMP-regulated chloride channel, whose mutations produce cystic fibrosis. The impairment of CFTR activity increases the intracellular Cl- concentration, which in turn produces an increased interleukin-1β (IL-1β) secretion. The secreted IL-1β then induces an autocrine positive feedback loop, further stimulating IL-1β priming and secretion. Since IL-1β can transactivate the epidermal growth factor receptor (EGFR), we study here the levels of expression for different EGFR ligands in Caco-2/pRS26 cells (expressing shRNA against CFTR resulting in a reduced CFTR expression and activity). The epiregulin (EREG), amphiregulin (AREG) and heparin binding EGF like growth factor (HBEGF) mRNAs, were found overexpressed in Caco-2/pRS26 cells. The EREG mRNA had the highest differential expression and was further characterized. In agreement with its mRNA levels, Western blots (WB) showed increased EREG levels in CFTR-impaired cells. In addition, EREG mRNA and protein levels were stimulated by incubation with exogenous IL-1β and inhibited by the Interleukin 1 receptor type I (IL1R1) antagonist IL1RN, suggesting that the overexpression of EREG is a consequence of the autocrine IL-1β loop previously described for these cells. In addition, the JNK inhibitor SP600125, and the EGFR inhibitors AG1478 and PD168393, also had an inhibitory effect on EREG expression, suggesting that EGFR, activated in Caco-2/pRS26 cells, is involved in the observed EREG upregulation. In conclusion, in Caco-2 CFTR-shRNA cells, the EGFR ligand EREG is overexpressed due to an active IL-1β autocrine loop that indirectly activates EGFR, constituting new signaling effectors for the CFTR signaling pathway, downstream of CFTR, Cl- and IL-1β. Fil: Massip Copiz, María Macarena. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Clauzure, Mariangeles. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Valdivieso, Ángel Gabriel. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Santa Coloma, Tomás Antonio. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Wiley-liss, Div John Wiley & Sons Inc http://hdl.handle.net/11336/48628 Massip Copiz, María Macarena; Clauzure, Mariangeles; Valdivieso, Ángel Gabriel; Santa Coloma, Tomás Antonio; Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function; Wiley-liss, Div John Wiley & Sons Inc; Journal of Cellular Biochemistry; 119; 3; 11-2017; 1-34 0730-2312 CONICET Digital CONICET
title Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
spellingShingle Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
Massip Copiz, María Macarena
Cftr
Cystic-Fibrosis
Epiregulin-Ereg
Il-1beta
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
title_short Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
title_full Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
title_fullStr Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
title_full_unstemmed Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
title_sort Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function
author Massip Copiz, María Macarena
author_facet Massip Copiz, María Macarena
Clauzure, Mariangeles
Valdivieso, Ángel Gabriel
Santa Coloma, Tomás Antonio
author_role author
author2 Clauzure, Mariangeles
Valdivieso, Ángel Gabriel
Santa Coloma, Tomás Antonio
author2_role author
author
author
topic Cftr
Cystic-Fibrosis
Epiregulin-Ereg
Il-1beta
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
topic_facet Cftr
Cystic-Fibrosis
Epiregulin-Ereg
Il-1beta
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
description CFTR is a cAMP-regulated chloride channel, whose mutations produce cystic fibrosis. The impairment of CFTR activity increases the intracellular Cl- concentration, which in turn produces an increased interleukin-1β (IL-1β) secretion. The secreted IL-1β then induces an autocrine positive feedback loop, further stimulating IL-1β priming and secretion. Since IL-1β can transactivate the epidermal growth factor receptor (EGFR), we study here the levels of expression for different EGFR ligands in Caco-2/pRS26 cells (expressing shRNA against CFTR resulting in a reduced CFTR expression and activity). The epiregulin (EREG), amphiregulin (AREG) and heparin binding EGF like growth factor (HBEGF) mRNAs, were found overexpressed in Caco-2/pRS26 cells. The EREG mRNA had the highest differential expression and was further characterized. In agreement with its mRNA levels, Western blots (WB) showed increased EREG levels in CFTR-impaired cells. In addition, EREG mRNA and protein levels were stimulated by incubation with exogenous IL-1β and inhibited by the Interleukin 1 receptor type I (IL1R1) antagonist IL1RN, suggesting that the overexpression of EREG is a consequence of the autocrine IL-1β loop previously described for these cells. In addition, the JNK inhibitor SP600125, and the EGFR inhibitors AG1478 and PD168393, also had an inhibitory effect on EREG expression, suggesting that EGFR, activated in Caco-2/pRS26 cells, is involved in the observed EREG upregulation. In conclusion, in Caco-2 CFTR-shRNA cells, the EGFR ligand EREG is overexpressed due to an active IL-1β autocrine loop that indirectly activates EGFR, constituting new signaling effectors for the CFTR signaling pathway, downstream of CFTR, Cl- and IL-1β.
publishDate 2017
format article
status_str publishedVersion
url http://hdl.handle.net/11336/48628
identifier_str_mv Massip Copiz, María Macarena; Clauzure, Mariangeles; Valdivieso, Ángel Gabriel; Santa Coloma, Tomás Antonio; Epiregulin (EREG) is upregulated through an IL‐1β autocrine loop in Caco‐2 epithelial cells with reduced CFTR function; Wiley-liss, Div John Wiley & Sons Inc; Journal of Cellular Biochemistry; 119; 3; 11-2017; 1-34
0730-2312
CONICET Digital
CONICET
language eng
eu_rights_str_mv openAccess
publisher Wiley-liss, Div John Wiley & Sons Inc
institution Consejo Nacional de Investigaciones Científicas y Técnicas
collection CONICET Digital (CONICET)
reponame_str CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
_version_ 1878403188978089984
publishDateSort 2017
author_browse Clauzure, Mariangeles
Massip Copiz, María Macarena
Santa Coloma, Tomás Antonio
Valdivieso, Ángel Gabriel
publisherStr Wiley-liss, Div John Wiley & Sons Inc
score 6,9460754

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