PMID- 29091309
OWN - NLM
STAT- MEDLINE
DCOM- 20181009
LR  - 20181202
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 119
IP  - 3
DP  - 2018 Mar
TI  - Epiregulin (EREG) is upregulated through an IL-1beta autocrine loop in Caco-2 
      epithelial cells with reduced CFTR function.
PG  - 2911-2922
LID - 10.1002/jcb.26483 [doi]
AB  - 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-1beta (IL-1beta) 
      secretion. The secreted IL-1beta then induces an autocrine positive feedback loop, 
      further stimulating IL-1beta priming and secretion. Since IL-1beta 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-1beta 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-1beta 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-1beta autocrine loop that indirectly activates EGFR, constituting new 
      signaling effectors for the CFTR signaling pathway, downstream of CFTR, Cl(-) , 
      and IL-1beta.
CI  - (c) 2017 Wiley Periodicals, Inc.
FAU - Massip-Copiz, Macarena
AU  - Massip-Copiz M
AD  - The Laboratory of Cellular and Molecular Biology, Institute for Biomedical 
      Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of 
      Argentina (UCA), The National Scientific and Technical Research Council 
      (CONICET), Buenos Aires, Argentina.
FAU - Clauzure, Mariangeles
AU  - Clauzure M
AD  - The Laboratory of Cellular and Molecular Biology, Institute for Biomedical 
      Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of 
      Argentina (UCA), The National Scientific and Technical Research Council 
      (CONICET), Buenos Aires, Argentina.
FAU - Valdivieso, Angel G
AU  - Valdivieso AG
AD  - The Laboratory of Cellular and Molecular Biology, Institute for Biomedical 
      Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of 
      Argentina (UCA), The National Scientific and Technical Research Council 
      (CONICET), Buenos Aires, Argentina.
FAU - Santa-Coloma, Tomas A
AU  - Santa-Coloma TA
AUID- ORCID: 0000-0002-3266-1095
AD  - The Laboratory of Cellular and Molecular Biology, Institute for Biomedical 
      Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of 
      Argentina (UCA), The National Scientific and Technical Research Council 
      (CONICET), Buenos Aires, Argentina.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171124
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (CFTR protein, human)
RN  - 0 (EREG protein, human)
RN  - 0 (Epiregulin)
RN  - 0 (IL1B protein, human)
RN  - 0 (Interleukin-1beta)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - *Autocrine Communication
MH  - Caco-2 Cells
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/genetics/*metabolism
MH  - Epiregulin/*biosynthesis/genetics
MH  - Epithelial Cells/cytology/*metabolism
MH  - ErbB Receptors/genetics/metabolism
MH  - Humans
MH  - Interleukin-1beta/genetics/*metabolism
MH  - *Up-Regulation
OTO - NOTNLM
OT  - CFTR
OT  - IL-1beta
OT  - cystic-fibrosis
OT  - epiregulin/EREG
EDAT- 2017/11/02 06:00
MHDA- 2018/10/10 06:00
CRDT- 2017/11/02 06:00
PHST- 2017/03/06 00:00 [received]
PHST- 2017/10/31 00:00 [accepted]
PHST- 2017/11/02 06:00 [pubmed]
PHST- 2018/10/10 06:00 [medline]
PHST- 2017/11/02 06:00 [entrez]
AID - 10.1002/jcb.26483 [doi]
PST - ppublish
SO  - J Cell Biochem. 2018 Mar;119(3):2911-2922. doi: 10.1002/jcb.26483. Epub 2017 Nov 
      24.