Document Detail


Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Rα2.
MedLine Citation:
PMID:  21864478     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Progressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13Rα2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis.
METHODS: IL-10(-/-), IL-12/23(p40)(-/-), and IL-13Rα2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni.
RESULTS: Induction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13Rα2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection.
CONCLUSIONS: IL-10, IL-12p40, and IL-13Rα2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response.
Authors:
Margaret M Mentink-Kane; Allen W Cheever; Mark S Wilson; Satish K Madala; Lara Megan Beers; Thirumalai R Ramalingam; Thomas A Wynn
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2011-08-22
Journal Detail:
Title:  Gastroenterology     Volume:  141     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-21     Completed Date:  2012-02-06     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2200-9     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Disease Progression
Female
Hypertension, Portal / immunology
Inflammation / immunology
Interleukin-10 / deficiency,  genetics,  physiology*
Interleukin-12 Subunit p40 / deficiency,  genetics,  physiology*
Interleukin-13 Receptor alpha2 Subunit / deficiency,  genetics,  physiology*
Liver Cirrhosis / immunology*,  mortality,  parasitology
Mice
Mice, Inbred BALB C
Mice, Knockout
Occult Blood
Real-Time Polymerase Chain Reaction
Schistosomiasis mansoni / immunology*,  mortality,  parasitology
Grant Support
ID/Acronym/Agency:
MC_UP_A253_1028//Medical Research Council; ZIA AI000829-13/AI/NIAID NIH HHS; ZIA AI001019-04/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Interleukin-12 Subunit p40; 0/Interleukin-13 Receptor alpha2 Subunit; 130068-27-8/Interleukin-10
Comments/Corrections

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