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Chemical inhibition of TRAF6-TAK1 axis as therapeutic strategy of endotoxin-induced liver disease
- Source :
- Biomedicine & Pharmacotherapy, Vol 155, Iss , Pp 113688- (2022)
- Publication Year :
- 2022
- Publisher :
- Elsevier, 2022.
-
Abstract
- The liver is exposed to gut-derived bacterial endotoxin via portal circulation, and recognizes it through toll-like receptor 4 (TLR4). Endotoxin lipopolysaccharide (LPS) stimulates the self-ubiquitination of ubiquitin ligase TRAF6, which is linked to scaffold with protein kinase TAK1 for auto-phosphorylation and subsequent activation. TAK1 activity is a signal transducer in the activating pathways of transcription factors NF-κB and AP-1 for production of various cytokines. Here, we hypothesized that TRAF6-TAK1 axis would be implicated in endotoxin-induced liver disease. Following exposure to endotoxin LPS, TLR4-mediated phosphorylation of TAK1 and transcription of cell-death cytokine TNF-α were triggered in Kupffer cells but not in hepatocytes as well as TNF receptor-mediated and caspase-3-executed apoptosis was occurred in D-galactosamine (GalN)-sensitized hepatocytes under co-culture with Kupffer cells. Treatment with pyridinylmethylene benzothiophene (PMBT) improved endotoxin LPS-induced hepatocyte apoptosis in GalN-sensitized C57BL/6 mice via suppressing NF-κB- and AP-1-regulated expression of TNF-α in Kupffer cells, and rescued the mice from hepatic damage-associated bleeding and death. As a mechanism, PMBT directly inhibited Lys 63-linked ubiquitination of TRAF6, and mitigated scaffold assembly between TRAF6 and the TAK1-activator adaptors TAB1 and TAB2 complex in Kupffer cells. Thereby, PMBT interrupted TRAF6 ubiquitination-induced activation of TAK1 activity in the TLR4-mediated signal cascade leading to TNF-α production. However, PMBT did not directly affect the apoptotic activity of TNF-α on GalN-sensitized hepatocytes. Finally, we propose chemical inhibition of TRAF6-TAK1 axis in Kupffer cells as a strategy for treating liver disease due to gut-derived endotoxin or Gram-negative bacterial infection.
Details
- Language :
- English
- ISSN :
- 07533322
- Volume :
- 155
- Issue :
- 113688-
- Database :
- Directory of Open Access Journals
- Journal :
- Biomedicine & Pharmacotherapy
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.7f0ca3c3868e43278bf09201eba4fdf5
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.biopha.2022.113688