HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production
© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
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| Enthalten in: |
FASEB journal : official publication of the Federation of American Societies for Experimental Biology - 37(2023), 9 vom: 24. Sept., Seite e23140 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kong, Xiangrong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.08.2023 Date Revised 29.08.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1096/fj.202300428RR |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production |
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| 520 | |a © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HIF-1α inhibitor | |
| 650 | 4 | |a acute liver failure | |
| 650 | 4 | |a cell death | |
| 650 | 4 | |a interleukin-1β | |
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| 700 | 1 | |a Liu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xinwen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Chendong |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Long |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jinxia |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Zhifu |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jingya |e verfasserin |4 aut | |
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