Hepatocyte Bcl-3 protects from death-receptor mediated apoptosis and subsequent acute liver failure.

Autor: Gehrke N; Department of Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Wörns MA; Department of Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Department of Gastroenterology, Hematology, Oncology and Endocrinology, Klinikum Dortmund, Dortmund, Germany., Mann A; Department of Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Hövelmeyer N; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Waisman A; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Straub BK; Institute of Pathology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Galle PR; Department of Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Schattenberg JM; Department of Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. joern.schattenberg@unimedizin-mainz.de.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 May 31; Vol. 13 (5), pp. 510. Date of Electronic Publication: 2022 May 31.
DOI: 10.1038/s41419-022-04946-y
Abstrakt: Acute liver failure (ALF) is a rare entity but exhibits a high mortality. The mechanisms underlying ALF are not completely understood. The present study explored the role of the hepatic B cell leukemia-3 (Bcl-3), a transcriptional regulator of nuclear factor-kappa B (NF-κB), in two independent models of ALF. We employed a recently developed transgenic mouse model in a C57BL6/J background comparing wild-type (WT) and transgenic littermates with hepatocyte-specific overexpression of Bcl-3 (Bcl-3 Hep ) in the ALF model of d-galactosamine (d-GalN) and lipopolysaccharide (LPS). Additionally, the apoptosis-inducing CD95 (FAS/APO-1)-ligand was explored. Bcl-3 Hep mice exhibited a significant protection from ALF with decreased serum transaminases, decreased activation of the apoptotic caspases 8, 9, and 3, lower rates of oxidative stress, B-cell lymphoma 2 like 1 (BCL2L1/BCL-X L ) degradation and accompanying mitochondrial cytochrome c release, and ultimately a decreased mortality rate from d-GalN/LPS compared to WT mice. d-GalN/LPS treatment resulted in a marked inflammatory cytokine release and stimulated the activation of signal transducer and activator of transcription (STAT) 3, c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinase (ERK) signaling comparably in the hepatic compartment of Bcl-3 Hep and WT mice. However, in contrast to the WT, Bcl-3 Hep mice showed a diminished rate of IkappaB kinase-beta (IKK-β) degradation, persistent receptor interacting protein kinase (RIPK) 1 function and thus prolonged cytoprotective nuclear factor-kappa B (NF-κB) p65 signaling through increased p65 stability and enhanced transcription. Likewise, Bcl-3 overexpression in hepatocytes protected from ALF with massive hepatocyte apoptosis induced by the anti-FAS antibody Jo2. The protection was also linked to IKK-β stabilization. Overall, our study showed that Bcl-3 rendered hepatocytes more resistant to hepatotoxicity induced by d-GalN/LPS and FAS-ligand. Therefore, Bcl-3 appears to be a critical regulator of the dynamics in ALF through IKK-β.
(© 2022. The Author(s).)
Databáze: MEDLINE
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