Na+/H+exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH2-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-α, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-γ and IFN-β were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-α and IL-1β also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

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The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice

Hepatology ◽

10.1002/hep.29145 ◽

2017 ◽

Vol 66 (3) ◽

pp. 869-884 ◽

Cited By ~ 43

Author(s):

Xiaojiaoyang Li ◽

Runping Liu ◽

Jing Yang ◽

Lixin Sun ◽

Luyong Zhang ◽

...

Keyword(s):

Multidrug Resistance ◽

Liver Injury ◽

Knockout Mice ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Gene Knockout ◽

Gender Disparity ◽

Gene Knockout Mice ◽

Cholestatic Liver Injury

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Mo1376 - Therapeutic Effects of Microrna-21 Depletion on Inflammatory Response in Liver Macrophages During Cholestatic Liver Injury

Gastroenterology ◽

10.1016/s0016-5085(18)33924-6 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-1186-S-1187

Author(s):

Keisaku Sato ◽

Lindsey Kennedy ◽

Thao Giang ◽

Tianhao Zhou ◽

Sugeily Ramos-Lorenzo ◽

...

Keyword(s):

Liver Injury ◽

Inflammatory Response ◽

Therapeutic Effects ◽

Liver Macrophages ◽

Cholestatic Liver Injury

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Peroxisome proliferator-activated receptor-α regulates postischemic liver injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00191.2003 ◽

2004 ◽

Vol 286 (4) ◽

pp. G606-G612 ◽

Cited By ~ 41

Author(s):

Tomohisa Okaya ◽

Alex B. Lentsch

Keyword(s):

Liver Injury ◽

Inflammatory Response ◽

Proinflammatory Cytokines ◽

Knockout Mice ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Peroxisome Proliferator ◽

Wild Type ◽

Peroxisome Proliferator Activated Receptor ◽

Proinflammatory Mediators

Peroxisome proliferator-activated receptor-α (PPARα) is a transcription factor that in some in vitro systems has been linked with downregulation of proinflammatory mediators, thus implicating a potential role for PPARα in the regulation of inflammatory processes. Hepatic ischemia-reperfusion injury is characterized by an intense acute inflammatory response that is dependent on a number of proinflammatory mediators. PPARα is abundantly expressed in hepatic parenchymal cells but not in Kupffer cells. This study examined whether PPARα is involved in regulation of the hepatic inflammatory response to ischemia-reperfusion. Mice nullizygous for PPARα had significantly greater liver injury than did their wild-type counterparts. Consistent with these findings, C57BL/6 mice treated with the PPARα agonist, WY-14643, had significantly less liver injury than mice receiving vehicle. PPARα-knockout mice also had greatly augmented liver neutrophil accumulation and modest increases in activation of the transcription factors NF-κB and activator protein-1. However, these effects were not associated with increased expression of proinflammatory cytokines or chemokines. In addition, PPARα-knockout mice expressed far less inducible nitric oxide synthase in liver than did wild-type mice after ischemia-reperfusion. Finally, treatment of cultured murine hepatocytes with WY-14643, a specific agonist of PPARα, protected cells against oxidant-induced injury. The data suggest that PPARα is an important regulator of the hepatic inflammatory response to ischemia-reperfusion in a manner that is independent of proinflammatory cytokines.

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Abstract #1005: Oral Iodine for Treatment of Decompensated Hyperthyroidism in Methimazole Induced Cholestatic Liver Injury

Endocrine Practice ◽

10.1016/s1530-891x(20)44127-8 ◽

2017 ◽

Vol 23 ◽

pp. 211-212

Author(s):

Abhijana Karunakaran ◽

Kristin Criner ◽

Jonathan Anolik

Keyword(s):

Liver Injury ◽

Cholestatic Liver Injury

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Bid-mediated apoptosis does not contribute to cholestatic liver injury following bile duct ligation

Zeitschrift für Gastroenterologie ◽

10.1055/s-0029-1191793 ◽

2009 ◽

Vol 47 (01) ◽

Author(s):

P Nalapareddy ◽

S Schüngel ◽

MP Manns ◽

H Jaeschke ◽

A Vogel

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Bile Duct Ligation ◽

Duct Ligation ◽

Cholestatic Liver Injury

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Combined function of c-Jun N-terminal kinases in hepatocytes protects mice from fibrosis development during cholestatic liver injury

10.1055/s-0038-1677091 ◽

2019 ◽

Author(s):

MR Mohamed ◽

FJ Cubero ◽

G Zhao ◽

YA Nevzorova ◽

N Gassler ◽

...

Keyword(s):

Liver Injury ◽

Cholestatic Liver Injury

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

Cellular and Molecular Immunology ◽

10.1038/s41423-019-0318-x ◽

2019 ◽

Vol 17 (12) ◽

pp. 1245-1256 ◽

Cited By ~ 7

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.

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