Abstract |
The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high-frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages is promoted by both oxygen-dependent and oxygen-independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin-1β (IL-1β). IL-1β further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL-1R) on hepatocyte. HIF-1α knockout in macrophages or IL-1R knockout in hepatocytes protects against liver failure. However, whether HIF-1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF-1α inhibitor PX-478 inhibits the expression and secretion of IL-1β, but not tumor necrosis factor α (TNFα), in bone marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX-478 combined with TNFα neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken together, our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF.
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Authors | Xiangrong Kong, Wei Liu, Xinwen Zhang, Chendong Zhou, Xinyu Sun, Long Cheng, Jinxia Lin, Zhifu Xie, Jingya Li |
Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology
(FASEB J)
Vol. 37
Issue 9
Pg. e23140
(09 2023)
ISSN: 1530-6860 [Electronic] United States |
PMID | 37584647
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. |
Chemical References |
- 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
- Tumor Necrosis Factor-alpha
- Lipopolysaccharides
- Hypoxia-Inducible Factor 1, alpha Subunit
- Oxygen
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Topics |
- Mice
- Animals
- Tumor Necrosis Factor-alpha
(metabolism)
- Lipopolysaccharides
(metabolism)
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Liver Failure, Acute
(chemically induced, pathology)
- Macrophages
(metabolism)
- Inflammation
(metabolism)
- Necrosis
(metabolism)
- Oxygen
(metabolism)
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