Inverse association between hepatic stellate cell apoptosis and fibrosis in chronic hepatitis C virus infection

Gonzalez, Stevan A.; Fiel, M. Isabel; Sauk, John J.; Canchis, P. Wilfredo; Liu, R.-C.; Chiriboga, Luis; Yee, Herman; Jacobson, Ira M.; Talal, Andrew H.

doi:10.1111/j.1365-2893.2008.01052.x

Cited by 27 publications

(17 citation statements)

References 40 publications

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“…Additionally, genes known to be expressed by activated HSCs, such as Bcl-2 associated X (BAX), which are also related to chemoattraction and apoptotic induction were upregulated. This contrasts with the downregulation of genes associated with inhibition of apoptosis (such as baculovirus IAP repeat-containing 5 [BIRC5]) and cell cycle progression (such as p21-activated kinase 7 [PAK7] and kinesin family member 11 [KIF11] and is consistent with a report that HSC apoptosis is anticorrelated with HCV-induced fibrogenesis (Gonzalez et al, 2009a). Taken together, these findings suggest that in HCV/HIV coinfected patients, increased migration of activated immune effector cells likely contributes to increased hepatic inflammation.…”

Section: Resultssupporting

confidence: 88%

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

et al. 2012

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Hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfected patients demonstrate accelerated progression to severe liver injury in comparison to HCV monoinfected patients, although the underlying mechanisms are unclear owing to infection of separate tissue compartments with two distinct viral pathogens. Microarray analysis of paired liver biopsy and peripheral blood mononuclear cell (PBMC) specimens from HCV/HIV coinfected and HCV monoinfected patients identified a gene expression signature associated with increased inflammation and immune activation that was present only in liver and PBMC samples from coinfected patients. We also identified in these samples liver- and PBMC-specific signatures enriched with fibrogenic/hepatic stellate activation and proinflammatory genes, respectively. Finally, Bayesian networks were constructed by assimilating these data with existing data from liver and PBMC samples from other cohorts, augmenting enrichment of biologically important pathways and further indicating that chronic immune activation in HCV/HIV coinfection may exacerbate liver disease progression in coinfected patients.

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Section: Resultssupporting

confidence: 88%

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

et al. 2012

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“…In addition, we found colocalization of a-SMA (marker for activated HSCs) and active caspase-3 (marker for apoptosis) in the liver biopsy specimens from HCV-positive patients, indicating that HSC apoptosis indeed occurs in HCV( þ ) livers. Accordingly, Gonzalez et al 26 recently demonstrated intra-hepatic HSC apoptosis to be inversely correlated with the stage of fibrosis in chronic HCV. Finally, we observed an inverse correlation between NK cell-induced HSC apoptosis and the stage of liver fibrosis, with significantly higher anti-HSC activity of NK cells in patients without fibrosis than in patient with F1/F2 and F3/F4 fibrosis, respectively.…”

Section: Discussionmentioning

confidence: 99%

NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner

Glässner

Eisenhardt

Krämer

et al. 2012

Laboratory Investigation

134

114

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In mouse models it has been shown that natural killer (NK) cells can attenuate liver fibrosis via killing of activated hepatic stellate cells (HSCs) in a NKG2D-and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. However, only little data exist regarding interactions of human NK cells with HSCs and their potential role in hepatitis C virus (HCV)-associated fibrogenesis. Therefore, purified NK cells from untreated HCV RNA( þ ) patients (n ¼ 33), interferon-a (IFN-a)-treated patients (n ¼ 17) and healthy controls (n ¼ 18) were coincubated with activated primary HSCs, and were tested for degranulation (CD107a expression) and secretion of IFN-g and TNF-a, respectively. Induction of HSC apoptosis was analyzed using an active caspase-3 assay. We found that following coincubation with HSCs a significant increase in CD107a expression could be observed in both NK cells from HCV( þ ) patients and healthy controls, whereas only negligible secretion of IFN-g and TNF-a could be detected. More importantly, NK cells from untreated HCV RNA( þ ) patients were significantly more effective in induction of HSC apoptosis (17.8 ± 9.2%) than NK cells from healthy controls (6.2 ± 2.1%; Po0.0001). Additionally, we observed an inverse correlation of liver fibrosis stage and the ability of NK cells to induce HSC apoptosis. Induction of HSC apoptosis was contact dependent and could partly be blocked by antibodies specific for TRAIL, NKG2D and FasL, respectively. It is noteworthy that NK cells from IFN-a-treated HCV( þ ) patients displayed the highest capability to kill HSCs (27.6±10.5%). Accordingly, pre-stimulation of NK cells with recombinant IFN-a significantly increased the ability of NK cells to induce cell death in primary HSCs and was dependent on upregulated expression of TRAIL. Here we demonstrate that NK cells from HCV-infected patients are highly efficient in inducing apoptosis of activated HSCs. Thus, NK cells may have an important anti-fibrotic role in chronic hepatitis C.

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“…Thus, the removal of activated HSCs is the primary hepatic fibrosis treatment strategy. Many recent studies have focused on the apoptosis of activated HSCs, indicating that this apoptosis mainly contributes to the reversal of hepatic fibrosis [4], [5]. Therefore, the induction of apoptosis in activated HSCs may be an effective hepatic fibrosis treatment strategy.…”

Section: Introductionmentioning

confidence: 99%

Schistosoma japonicum Soluble Egg Antigens Facilitate Hepatic Stellate Cell Apoptosis by Downregulating Akt Expression and Upregulating p53 and DR5 Expression

Wang

Zhu

et al. 2014

PLoS Negl Trop Dis

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BackgroundThe induction of hepatic stellate cell (HSC) apoptosis has potential as a potent strategy to diminish the progression of liver fibrosis. Previous studies have demonstrated the ability of soluble egg antigens (SEA) from schistosomes to inhibit HSC activation and to induce apoptosis in vitro. In this study, we aimed to explore the mechanism of SEA-induced apoptosis in HSCs.Methodology/Principal FindingsIn this study, we found that SEA could upregulate p53 and DR5 and downregulate the p-Akt. The apoptosis of HSCs induced by SEA could be reduced in HSCs that were treated with p53-specific siRNA and in HSCs that were treated with DR5-specific shRNA. In addition, GW501516, which enhances the expression of Akt, could also decrease the SEA-induced HSC apoptosis. We also found that the increased expression of p53 and DR5 induced by SEA through Mdm2 were reduced by GW501516.Conclusions/SignificanceOur data suggest that SEA can induce HSC apoptosis by downregulating Akt expression and upregulating p53-dependent DR5 expression.

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Inverse association between hepatic stellate cell apoptosis and fibrosis in chronic hepatitis C virus infection

Cited by 27 publications

References 40 publications

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner

Schistosoma japonicum Soluble Egg Antigens Facilitate Hepatic Stellate Cell Apoptosis by Downregulating Akt Expression and Upregulating p53 and DR5 Expression

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