IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.
Animals
Carcinogenesis
/ chemically induced
Carcinoma, Hepatocellular
/ chemically induced
Disease Models, Animal
Ethanol
/ adverse effects
Gene Deletion
Hepatocytes
/ metabolism
Humans
Interleukin-17
/ metabolism
Kupffer Cells
/ metabolism
Liver Cirrhosis
/ complications
Liver Diseases, Alcoholic
/ complications
Liver Neoplasms
/ chemically induced
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, Interleukin-17
/ deficiency
Signal Transduction
/ genetics
Transcriptome
ALD
Alcoholic liver disease
Cholesterol synthesis
Fibrosis
HCC
Hepatocellular carcinoma
IL-17 signaling
Inflammation
Mutational signatures
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
11
06
2019
revised:
04
12
2019
accepted:
09
12
2019
pubmed:
4
1
2020
medline:
7
10
2021
entrez:
4
1
2020
Statut:
ppublish
Résumé
Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
Sections du résumé
BACKGROUND & AIMS
Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.
METHODS
Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens.
RESULTS
We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra
CONCLUSIONS
Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.
LAY SUMMARY
IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
Identifiants
pubmed: 31899206
pii: S0168-8278(19)30761-5
doi: 10.1016/j.jhep.2019.12.016
pmc: PMC7167339
mid: NIHMS1556770
pii:
doi:
Substances chimiques
IL17A protein, human
0
Il17a protein, mouse
0
Il17ra protein, mouse
0
Interleukin-17
0
Receptors, Interleukin-17
0
Ethanol
3K9958V90M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
946-959Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK120714
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI043477
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA018663
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES010337
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211794
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA029019
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA028550
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK088837
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK111866
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099205
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA022614
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA027681
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI043477
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101737
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234128
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 European Association for the Study of the Liver. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare they have no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
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