Interleukin-9 attenuates inflammatory response and hepatocyte apoptosis in alcoholic liver injury

Life Sciences ◽  
2021 ◽  
pp. 120180
Author(s):  
Hongwu Meng ◽  
Ruowen Niu ◽  
Hongmei You ◽  
Ling Wang ◽  
Rui Feng ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Alcoholic Liver Injury ◽  
Hepatocyte Apoptosis ◽  
Interleukin 9

scholarly journals SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yingting Zhang ◽  
Xidai Long ◽  
Xin Ruan ◽  
Qian Wei ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Liver Injury ◽  
Protein Expression ◽  
Nicotinamide Adenine Dinucleotide ◽  
Target Gene ◽  
Alcoholic Liver Injury ◽  
Protein Acetylation ◽  
Hepatocyte Apoptosis ◽  
Enhancer Binding Protein

AbstractProtein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation–deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.

scholarly journals The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Pang ◽  
Hao Jin ◽  
Xiquan Ke ◽  
Zhongran Man ◽  
Yong Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Concanavalin A ◽  
Serum Levels ◽  
Hepatocyte Apoptosis ◽  
Con A ◽  
Serotonin 2A Receptor ◽  
Serotonin 2A

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.

Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress

2010 ◽  
Vol 59 (8) ◽  
pp. 635-645 ◽  
Author(s):  
Xiongwen Lv ◽  
Zhen Chen ◽  
Jun Li ◽  
Lei Zhang ◽  
Hongfeng Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Alcoholic Liver Injury ◽  
And Oxidative Stress

scholarly journals Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

2019 ◽  
Vol 17 (12) ◽  
pp. 1245-1256 ◽  
Author(s):  
Yuting Jin ◽  
Changyong Li ◽  
Dongwei Xu ◽  
Jianjun Zhu ◽  
Song Wei ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Inflammatory Injury ◽  
Notch1 Signaling ◽  
Caspase 1 ◽  
Hepatocellular Damage ◽  
Hepatocellular Apoptosis

AbstractNotch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

scholarly journals Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia

2021 ◽  
Vol 10 (12) ◽  
pp. 2718
Author(s):  
Omid Madadi-Sanjani ◽  
Gunnar Bohlen ◽  
Fabian Wehrmann ◽  
Julia Andruszkow ◽  
Karim Khelif ◽  
...  
Keyword(s):  
Liver Injury ◽  
Biliary Atresia ◽  
Caspase 3 ◽  
Serum Levels ◽  
Healthy Individuals ◽  
Serological Detection ◽  
Caspase Activation ◽  
Hepatocyte Apoptosis ◽  
Non Invasive ◽  
Cholestatic Diseases

In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA.

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