Author:
Kucsera Dániel,Tóth Viktória E.,Sayour Nabil V.,Kovács Tamás,Gergely Tamás G.,Ruppert Mihály,Radovits Tamás,Fábián Alexandra,Kovács Attila,Merkely Béla,Ferdinandy Péter,Varga Zoltán V.
Abstract
AbstractInterleukin-1β (IL-1β) is a key mediator of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of systemic inflammation-driven aging. IL-1β contributes to cardio-metabolic decline, and may promote hepatic oncogenic transformation. Therefore, IL-1β is a potential therapeutic target in these pathologies. We aimed to investigate the hepatic and cardiac effects of an IL-1β targeting monoclonal antibody in an aged mouse model of NASH. 24 months old male C57Bl/6J mice were fed with control or choline deficient (CDAA) diet and were treated with isotype control or anti-IL-1β Mab for 8 weeks. Cardiac functions were assessed by conventional—and 2D speckle tracking echocardiography. Liver samples were analyzed by immunohistochemistry and qRT-PCR. Echocardiography revealed improved cardiac diastolic function in anti-IL-1β treated mice with NASH. Marked hepatic fibrosis developed in CDAA-fed group, but IL-1β inhibition affected fibrosis only at transcriptomic level. Hepatic inflammation was not affected by the IL-1β inhibitor. PCNA staining revealed intensive hepatocyte proliferation in CDAA-fed animals, which was not influenced by neutralization of IL-1β. IL-1β inhibition increased hepatic expression of Pd-1 and Ctla4, while Pd-l1 expression increased in NASH. In conclusion, IL-1β inhibition improved cardiac diastolic function, but did not ameliorate features of NASH; moreover, even promoted hepatic immune checkpoint expression, with concomitant NASH-related hepatocellular proliferation.
Funder
New National Excellence Program of the Ministry of Human Capacities
‘Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése’
Gedeon Richter Excellence PhD Scholarship
National Heart Program
Momentum Research Grant
Horizon 2020 Research and Innovation Programme
Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology in Hungary
National Research, Development and Innovation Office of Hungary
Publisher
Springer Science and Business Media LLC
Cited by
2 articles.
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