Up-regulation of the expression of costimulatory molecule CD40 in hepatocytes by hepatitis B virus X antigen

Tang, Y.; Chen, Yongwen; Ni, Bing; Yang, Di; Guo, Sheng; Wu, Yuzhang

doi:10.1016/j.bbrc.2009.03.139

Cited by 9 publications

(5 citation statements)

References 31 publications

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“…19 Under pathological conditions, hepatocytes express CD40, which renders stimulation of CD40 signaling harmful. 20,21 Our nanoimmunotherapy does the opposite and — under pathological conditions — may therefore exert a therapeutic benefit. Having said that, blood chemistry analysis confirmed that TRAF6i-HDL had no toxic effect on the liver (Fig.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates

et al. 2018

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In atherosclerosis, macrophage accumulation is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T-lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6). We evaluated the biodistribution characteristics of the nanoimmunotherapy in Apolipoprotein E deficient (Apoe−/−) mice and in non-human primates by in vivo PET imaging. In Apoe−/− mice, a one-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, caused by the impaired migration capacity of monocytes, as established by transcriptome analysis. The rapid reduction of plaque inflammation by the TRAF6-targeted nanoimmunotherapy and its favourable toxicity profiles in both mice and non-human primates highlights the translational potential of this strategy for the treatment of atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates

et al. 2018

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“…7C to E). The effect of parenchymal CD40 expression was not limited to these two molecules in the B7 superfamily (17); in transgenic mice, the relative copy numbers of PD-L1 (B7-H1) and B7-H4 mRNA were 2.71- ( p < 0.01) and 1.84-fold ( p > 0.05), respectively, over those in non-transgenics (Supp. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In mice, disruption of co-stimulatory molecule PD-L1 resulted in impaired CD8 + T cell contraction, leading to accelerated hepatocyte damage and hepatitis (37). In co-stimulatory signaling pathways, CD40 is located upstream of CD80 and CD86; however, whether it interacts with other molecules, including PD-L1, B7-H4 and E-selectin remains unclear (17). …”

Section: Discussionmentioning

confidence: 99%

Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice

et al. 2011

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The healthy adult human liver expresses low levels of major histocompatibility complex class II (MHC II) and undetectable levels of immune costimulatory molecules. However, high levels of MHC II, CD40, and B7 family molecules are expressed in the activated Kupffer cells and hepatocytes of patients with viral hepatitis. The precise role of these molecules in viral clearance and immune-mediated liver injury is not well understood. We hypothesized that parenchymal CD40 expression enhances T cell recruitment and effector functions, which may facilitate viral clearance and alleviate liver injury. To test this hypothesis, we generated novel liver-specific, conditional CD40 transgenic mice, and we challenged them intravenously with a recombinant replication-deficient adenovirus carrying Cre recombinase (AdCre). Wild-type mice infected with AdCre developed a relatively mild course of viral hepatitis and recovered spontaneously. CD40 expression in the livers of transgenic animals, however, resulted in CD80 and CD86 expression. The dysregulation of population dynamics and effector functions of intrahepatic lymphocytes (IHLs) resulted in severe lymphocytic infiltration, apoptosis, necroinflammation, and serum alanine aminotransferase elevations in a dose-dependent fashion. To our surprise, an early expansion and subsequent contraction of IHLs (especially CD8 1 and natural killer cells), accompanied by increased granzyme B and interferon-c production, did not lead to faster viral clearance in CD40 transgenic mice. Conclusion: Our results demonstrate that hepatic CD40 expression does not accelerate adenoviral clearance but rather exacerbates liver injury. This study unveils a previously unknown deleterious effect of hepatic CD40 on adenovirus-induced liver inflammation. (HEPATOLOGY 2011;53:1455-1467 A denoviruses are responsible for approximately 5% of all upper respiratory infections and for considerable numbers of cases of gastroenteritis in the developing world and among immunosuppressed individuals globally. In addition to their role as important pathogens, recombinant adenoviruses, especially adenovirus serotype 5 (Ad5), are among the preferred vectors for gene therapy and experimental vaccines for human

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“…The CD40-CD40LG interaction was crucial in the activation of antigen-presenting cells and in the initiation of humoral and cellular immune responses (34). Studies demonstrated that CD40LG-mediated immune gene therapy for HCC was an effective treatment as it activated the humoral and cellular immune systems (35,36). In addition, PRKCZ has been proposed to induce hepatocyte growth factor to regulate the CXCR4-CXC ligand 12, which has been demonstrated to…”

Section: Discussionmentioning

confidence: 99%

Identification of the typical miRNAs and target genes in hepatocellular carcinoma

Han

Zhao

et al. 2014

Molecular Medicine Reports

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The aim of the present study was to identify miRNAs that were differentially expressed in hepatocellular carcinoma (HCC) by comparing normal and cancer tissue samples and to analyze the correlation of the target genes and HCC. The gene expression profile of GSE31383 was downloaded from the Gene Expression Omnibus database, including 19 samples, 9 normal and 10 from HCC tissue samples. The differentially‑expressed miRNAs were identified with packages in R language and further analyzed using bioinformatics methods. Firstly, the verified targets of miRNAs were integrated in two miRNA databases: miRecords and miRTarBase, and the targets of the differentially‑expressed miRNAs were obtained. The software STRING was then used to construct the interaction network of target genes. Finally, a functional enrichment analysis of the genes in the interaction network was conducted using the software Gestalt. Typical miR‑224 and miR‑214 were identified by comparing normal and cancer samples, each of which obtained 14 and 8 target genes, respectively. The functional enrichment analysis of the targets in the two groups highlighted the intracellular signaling cascade. In conclusion, the featured miRNAs (the upregulated miRNA‑224 and downregulated miRNA‑214) and their target genes are significant in the occurrence and development of HCC, which is likely to be significant for the identification of therapeutic targets and biomarkers to aid in the treatment of HCC.

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Up-regulation of the expression of costimulatory molecule CD40 in hepatocytes by hepatitis B virus X antigen

Cited by 9 publications

References 31 publications

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates

Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice

Identification of the typical miRNAs and target genes in hepatocellular carcinoma

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