A novel role for interleukin 32 in cholestasis

Li, Ling; Zhao, Nan; Pan, Qiong; Zhang, Liangjun; Zhang, Xiaoxun; Li, Xuan; Liao, Min; Li, Qiao; Huang, Xinglin; Chen, Sheng; Li, Jianwei; Wang, Huaizhi; Huang, Xuequan; Fan, Shijun; Li, Man; Chai, Jin

doi:10.1002/ctm2.594

Cited by 5 publications

(16 citation statements)

References 11 publications

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“…Furthermore, we did a literature search, but there were no publications on the interaction between FXR and TNFRSF12A . However, our previous studies have demonstrated that conjugated BAs activate hepatic JNK signaling in human cholestasis [ 26 , 27 ]. JNK-mediated phosphorylation enhances the activity of transcription factor c-JUN, a component of the AP-1 transcription factor to induce transcription [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, our previous studies have demonstrated that conjugated BAs activate hepatic JNK signaling in human cholestasis [ 26 , 27 ]. JNK-mediated phosphorylation enhances the activity of transcription factor c-JUN, a component of the AP-1 transcription factor to induce transcription [ 26 , 27 ]. Our recent report also indicates that BA-stressed hepatocytes activate NFAT, which can associate with AP-1 [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…7E ). Initially, the accumulated intrahepatic BAs during cholestasis activate the JNK signaling pathway [ 26 , 27 ] to stimulate TNFRSF12A expression at the transcriptional level through increasing the binding activity of c-JUN to the TNFRSF12A promoter. Subsequently, the elevation of TNFRSF12A triggers hepatocyte pyroptosis by the NFκB/Caspase-1/GSDMD signaling in cholestasis.…”

Section: Discussionmentioning

confidence: 99%

“…Abcb4 KO mice (Abcb4-KO, C57BL/6J background) were developed by Shanghai Model Organisms Center, Inc (Shanghai, China), as we previously reported [ 26 ]. Briefly, a deletion of 411 bp in exon 3 of the Abcb4 gene resulted in a frameshift mutation and gene inactivation in Abcb4 KO mice.…”

Section: Methodsmentioning

confidence: 99%

“…Primary mouse hepatocytes were isolated from 10- and 20-week-old mice using collagenase perfusion as previously described [ 26 ]. Fresh primary mouse hepatocytes were cultured or co-cultured in 5% FBS–Williams’ Medium E and subsequently treated with 100 μM conjugated BAs or 100 ng/ml TWEAK (Peprotech, NJ, USA) for 12 or 24 h. Finally, whole cell lysates were collected as described previously [ 26 , 29 ] for subsequent real-time qPCR and Western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

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Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis

Liao

et al. 2023

Cell Death Discov.

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Tumor necrosis factor receptor superfamily member-12A (TNFRSF12A) plays a critical role in inflammation and cell death. It is expressed in multiple tissues yet extremely low in normal liver. To date, little is known about its role in cholestasis. Therefore, we sought to delineate the role of TNFRSF12A in cholestasis and its underlying mechanisms. Human liver tissues were collected from patients with obstructive cholestasis (OC) or primary biliary cholangitis (PBC). Tnfrsf12a knockout (KO) mice were generated. Cholestasis was induced by bile-duct ligation (BDL) or 0.1% 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-feeding. Human hepatoma PLC/PRF/5-ASBT and THP1 cell lines or primary mouse hepatocytes were used for mechanistic studies. Hepatic TNFRSF12A expression was markedly increased in OC or PBC patients. Genetic ablation of Tnfrsf12a in BDL- and 0.1%DDC-induced cholestatic mice significantly attenuated cholestatic liver injury with remarkable reduction of hepatocyte pyroptosis but without changing scores of necroptosis and apoptosis. Morphological features of hepatocyte pyroptosis and increased levels of pyroptosis-related proteins, NLRP3, cleaved-Caspase-1, and cleaved-GSDMD in OC patients and BDL-mice confirmed this observation. Further mechanistic studies revealed that bile acids (BAs) induced TNFRSF12A expression by enhancing the transcription factor c-JUN binding to the TNFRSF12A promoter and subsequently initiated hepatocyte pyroptosis by the NFκB/Caspase-1/GSDMD signaling. Interestingly, TWEAK, a typical ligand of TNFRSF12A, secreted by infiltrated macrophages in cholestatic livers, enhanced TNFRSF12A-induced hepatocyte pyroptosis. Taken together, we report, for the first time, that hepatic TNFRSF12A is dramatically increased in human cholestasis. Deletion of TNFRSF12A inhibits BAs-induced hepatocyte pyroptosis through the NFκB/Caspase-1/GSDMD signaling and thereby ameliorates cholestatic liver injury. As such, targeting TNFRSF12A could be a promising approach to treating cholestasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis

Liao

et al. 2023

Cell Death Discov.

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Fluorofenidone ameliorates cholestasis and fibrosis by inhibiting hepatic Erk/-Egr-1 signaling and Tgfβ1/Smad pathway in mice

Wang

Zhang

et al. 2022

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Runt-related transcription factor-1 ameliorates bile acid–induced hepatic inflammation in cholestasis through JAK/STAT3 signaling

et al. 2023

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Background and Aims: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. Approach and Results: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5-ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1-P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2, and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid–induced CCL2 and CXCL2 in hepatocytes. Conclusions: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

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A novel role for interleukin 32 in cholestasis

Cited by 5 publications

References 11 publications

Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis

Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis

Fluorofenidone ameliorates cholestasis and fibrosis by inhibiting hepatic Erk/-Egr-1 signaling and Tgfβ1/Smad pathway in mice

Runt-related transcription factor-1 ameliorates bile acid–induced hepatic inflammation in cholestasis through JAK/STAT3 signaling

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