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author:("Zheng, sunun")
1.  Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-β is critical for immune homeostasis following acute liver injury 
During the acute liver injury, immune responses are provoked into eliciting inflammation in the acute phase. In the healing phase, the inflammation is terminated for wound healing and restoration of immune homeostasis. In this study, we sought to address how regulatory T cells (Tregs) are involved in the progression of liver injury and repair. In the acute phase, intrahepatic Tregs (CD4+FoxP3+Helios+) diminished promptly through apoptosis, which was followed by inflammation and tissue injury. In the healing phase, a new subset of Tregs (CD4+Foxp3+Helios−) was generated in correlation with the matrix metalloproteinase (MMP) cascade and transforming growth factor-beta (TGF-β) activation that were manifested mainly by hepatic stellate cells. Moreover, the induction of induced Tregs and wound healing were both impaired in mice lacking TGF-β signaling or MMPs. The depletion of induced Tregs also impeded wound healing for tissue repair. Together, this study demonstrates the mechanism that the loss of nTregs through apoptosis in the acute phase may facilitate inflammation, while regenerated Tregs through MMP9/13-dependent activation of TGF-β in the healing phase are critical to terminate inflammation and allow for wound healing.
PMCID: PMC3841112  PMID: 24280647
liver injury; wound healing; regulatory T cells; TGF-β; IL-1; hepatic stellate cells; matrix metalloproteinase
2.  Oxidative stress promotes d-GalN/LPS-induced acute hepatotoxicity by increasing glycogen synthase kinase 3β activity 
Inflammation Research  2014;63(6):485-494.
Our previous studies have demonstrated that glycogen synthase kinase 3β (GSK3β) activity is increased in the progression of acute liver failure (ALF), which aggravates liver injury, while its regulatory mechanism remains elusive. This study is designated to address whether oxidative stress activates GSK3β to promote ALF.
In a murine model induced by d-galactosamine (d-GalN) (700 mg/kg) and LPS (10 μg/kg), N-acetylcysteine (300 mg/kg) or SB216763 (25 mg/kg) was used to inhibit oxidative stress or GSK3β activity, respectively. Serum alanine aminotransferase and aspartate aminotransferase levels were assessed. The parameters of oxidative stress were evaluated in liver tissue. Whether GSK3β inhibition protects hepatocytes from oxidative stress-induced cell apoptosis was investigated in vitro. Moreover, the activity of GSK3β was measured in the liver of chronic hepatitis B (CHB) patients and ALF patients.
In vivo, N-acetylcysteine ameliorated the d-GalN/LPS-induced hepatotoxicity and reduced GSK3β activity; GSK3β inhibition increased hepatic superoxide dismutase activity and the glutathione content, decreased malondialdehyde production in the liver tissues; while GSK3β inhibition suppressed the JNK activation in the liver and decreased cytochrome c release from mitochondria. In vitro, GSK3β inhibition lessened hepatocytes apoptosis induced by H2O2 or Antimycin A, as demonstrated by decreased LDH activity, and reduced cleavage of caspase-3 expression. Furthermore, GSK3β activity in the CHB patients was increased in the phase of ALF.
Results indicate that GSK3β activation contributes to liver injury by participating in oxidative stress response in ALF and is, therefore, a potential therapeutic target for ALF.
PMCID: PMC4018480  PMID: 24531650
GSK3β; SB216763; Acute liver failure; Oxidative stress; N-acetylcysteine
3.  Inhibition of Glycogen Synthase Kinase 3β Ameliorates D-GalN/LPS-Induced Liver Injury by Reducing Endoplasmic Reticulum Stress-Triggered Apoptosis 
PLoS ONE  2012;7(9):e45202.
Glycogen synthase kinase 3β(GSK3β) is a ubiquitous serine-threonine protein kinase that participates in numerous cellular processes and disease pathophysiology. We aimed to determine therapeutic potential of GSK3β inhibition and its mechanism in a well-characterized model of lipopolysaccharide (LPS)-induced model of acute liver failure (ALF).
In a murine ALF model induced by D-GalN(700 mg/kg)/LPS(10 µg/kg), we analyzed GSK3β mechanisms using a specific chemical inhibitor, SB216763, and detected the role of endoplasmic reticulum stress (ERS). Mice were administered SB216763 at 2 h before or after D-GalN/LPS injection, respectively, and then sacrificed 6 h after D-GalN/LPS treatment to evaluate its prophylactic and therapeutic function. The lethality rate, liver damage, ERS, cytokine expression, MAP kinase, hepatocyte apoptosis and expression of TLR 4 were evaluated, respectively. Whether the inhibition of GSK3β activation protected hepatocyte from ERS-induced apoptosis was investigated in vitro.
Principal Findings
GSK3β became quickly activated (dephosphorylated) upon D-GalN/LPS exposure. Administration of SB216763 not only ameliorated liver injury, as evidenced by reduced transaminase levels, and well-preserved liver architecture, but also decreased lethality. Moreover, GSK3β inhibition resulted in down-regulation of pro-apoptotic proteins C/EBP–homologous protein(CHOP) and caspase-12, which are related to ERS. To further demonstrate the role of ERS, we found that GSK3β inhibition protected hepatocyte from ERS-induced cell death. GSK3β inhibition down-regulated the MAPK pathways, reduced expression of inflammatory cytokines and decreased expression of TLR4.
Our findings demonstrate the key function of GSK3β signaling in the pathophysiology of ALF, especially in regulating the ERS, and provide a rationale for targeting GSK3β as a potential therapeutic strategy to ameliorate ALF.
PMCID: PMC3461002  PMID: 23028846
4.  Interleukin-1 as an Injury Signal Mobilizes Retinyl Esters in Hepatic Stellate Cells through Down Regulation of Lecithin Retinol Acyltransferase 
PLoS ONE  2011;6(11):e26644.
Retinoids are mostly stored as retinyl esters in hepatic stellate cells (HSCs) through esterification of retinol and fatty acid, catalyzed by lecithin-retinol acyltransferase (LRAT). This study is designated to address how retinyl esters are mobilized in liver injury for tissue repair and wound healing. Initially, we speculated that acute inflammatory cytokines may act as injury signal to mobilize retinyl esters by down-regulation of LRAT in HSCs. By examining a panel of cytokines we found interleukin-1 (IL-1) can potently down-regulate mRNA and protein levels of LRAT, resulting in mobilization of retinyl esters in primary rat HSCs. To simulate the microenvironment in the space of Disse, HSCs were embedded in three-dimensional extracellular matrix, by which HSCs retaine quiescent phenotypes, indicated by up-regulation of LRAT and accumulation of lipid droplets. Upon IL-1 stimulation, LRAT expression went down together with mobilization of lipid droplets. Secreted factors from Kupffer cells were able to suppress LRAT expression in HSCs, which was neutralized by IL-1 receptor antagonist. To explore the underlying mechanism we noted that the stability of LRAT protein is not significantly regulated by IL-1, indicating the regulation is likely at transcriptional level. Indeed, we found that IL-1 failed to down-regulate recombinant LRAT protein expressed in HSCs by adenovirus, while transcription of endogenous LRAT was promptly decreased. Following liver damage, IL-1 was promptly elevated in a close pace with down-regulation of LRAT transcription, implying their causative relationship. After administration of IL-1, retinyl ester levels in the liver, as measured by LC/MS/MS, decreased in association with down-regulation of LRAT. Likewise, IL-1 receptor knockout mice were protected from injury-induced down-regulation of LRAT. In summary, we identified IL-1 as an injury signal to mobilize retinyl ester in HSCs through down-regulation of LRAT, implying a mechanism governing transition from hepatic injury to wound healing.
PMCID: PMC3208544  PMID: 22073179

Results 1-4 (4)