Intrahepatic mRNA Expression of FAS, FASL, and FOXP3 Genes Is Associated with the Pathophysiology of Chronic HCV Infection

Amoras, Ednelza da Silva Graça; Gomes, Samara Tatielle Monteiro; Freitas, Felipe Bonfim; Ishak, Geraldo; Araújo, Marialva Tereza Ferreira de; Demachki, Sâmia; Conde, Simone Regina Souza da Silva; Ishak, Marluísa de Oliveira Guimarães; Ishak, Ricardo; Vallinoto, Antônio Carlos Rosário

doi:10.1371/journal.pone.0156604

Cited by 13 publications

(12 citation statements)

References 51 publications

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“…As Th17-derived IL-6 and IL-21 could block the differentiation of Tregs [ 47 ], we propose that increased expressions of IL-21 mRNA by IL-23 agonist could might have caused a corresponding reduction in the FoxP3 mRNA expressions. Importantly, our data on the mRNA expressions of IL-17A, IL-22, STAT1, SOCS3, MxA, and FoxP3 in the PBMCs are consistent with the changes of these cytokines in livers reported in other studies [ 48 , 49 , 50 , 51 , 52 ]. Our data also suggest that the imbalance of T-cell subsets distribution might have important influences on disease progression and clinical outcome.…”

Section: Discussionsupporting

confidence: 92%

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Meng

Zhao

Niu

et al. 2016

IJMS

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Interleukin-23 (IL-23) and its downstream factor IL-17 are the key cytokines involved in immune and inflammatory response in chronic liver diseases. This study aimed to investigate the role and molecular mechanisms of the IL-23/Th17 axis in chronic hepatitis C virus (HCV) infection, and the efficacy of IL-23/Th17 modulation in response to anti-HCV therapy. Sixty-six HCV-infected patients and 20 healthy controls were enrolled. The patients received PegIFNa-2a and ribavirin therapy for at least 48 weeks. The plasma level of IL-23 and the number of IL-17A-, IFN-γ-, and IL-21-producing peripheral blood mononuclear cells (PBMCs) at baseline and 12, 24, and 48 weeks following treatment were determined. The mRNA level of Th17 immune-associated molecules in PBMCs was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) following treatment with IL-23 agonist or antagonist. Our data showed that, compared to healthy controls, HCV-infected patients had an increased plasma level of IL-23 and increased frequencies of IL-17A- and IFN-γ-producing PBMCs, whereas the HCV patients exhibited a reduced number of IL-21-producing PBMCs. However, the baseline frequencies of IL-21-producing PBMCs were markedly higher in HCV patients who achieved rapid virological response (RVR) than those without RVR. Additionally, the mRNA expressions of IL-21, IFN-γ, myxovirus resistance protein A (MxA), and suppressor of cytokine signaling 3 (SOCS3) were significantly upregulated in PBMCs, while FoxP3 expression was suppressed by IL-23 agonist. Thus, the IL-23/Th17 axis plays an important role in development of chronic HCV infection and antiviral response. IL-23 may enhance the antiviral activity of interferon-based therapy by modulating the expression of Th17 cells-associated molecules in HCV-infected patients.

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Section: Discussionsupporting

confidence: 92%

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Meng

Zhao

Niu

et al. 2016

IJMS

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“…In addition, certain Treg subsets stimulate fibrosis through the release of TGFβ. Recent studies have shown increased number of regulatory T cells in peripheral blood and in liver tissue of chronic HCV patients [28, 29]. Similarly, we found significantly higher number of Tregs in peripheral blood of all groups of patients in comparison to control, indicating strong suppression of immune response.…”

Section: Discussionsupporting

confidence: 80%

Chronic Hepatitis C: Conspectus of immunological events in the course of fibrosis evolution

et al. 2019

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In chronically infected HCV patients emergence and evolution of fibrosis, as a consequence of virus persistence, can be considered as an indicator of disease advancement. Therefore the aim of this study was to correlate alterations of immune response in chronic HCV patients with liver histopathology. Sera cytokine levels and frequency of circulating and liver infiltrating cells were evaluated using 13plex Kit Flow Cytomix, flow cytometry and immunohistochemistry. We found that the number of circulating T lymphocytes (including CD4+, CD8+ and Treg) and B lymphocytes, as well as DCs, was higher in patients with no fibrosis than in healthy subjects. In patients with fibrosis frequency of these cells decreased, and contrarily, in the liver, number of T and B lymphocytes gradually increased with fibrosis. Importantly, in patients with advanced fibrosis, liver infiltrating regulatory T cells and DC-SIGN+ mononuclear cells with immunosuppressive and wound-healing effector functions were abundantly present. Cytokine profiling showed predominance of proinflammatory cytokines in patients with no fibrosis and a tendency of decline in level of all cytokines with severity of liver injury. Lower but sustained IL-4 production refers to Th2 predominance in higher stages of fibrosis. Altogether, our results reveal graduall alterations of immunological parameters during fibrosis evolution and illustrate the course of immunological events through disease progression.

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“…The literature also provides data that correlate FOXP3 expression and the presence of Treg cells with higher levels of inflammatory activity and the degree of liver fibrosis in chronic viral hepatic diseases ( 74 – 76 ). Thus, in patients with chronic hepatitis C infection, the − 3279C > A polymorphism may mediate Treg activation in more advanced stages of liver inflammation and fibrosis, as shown by the relationships established in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, in the absence of Th2-specific signaling, FOXP3+ Treg cells can express high levels of IFN-γ and T-bet, which are Th1-specific transcription factors, making them susceptible to conversion to the Th1 profile ( 79 , 80 ). Reportedly, blockage of the Treg-Th2 conversion generated by the * G allele of the − 924A > G polymorphism ( 76 ) can promote an immune balance favorable to the development of a Th1 profile, which is considered crucial for the control of viral replication by tissue inflammation ( 81 , 82 ). This situation would lead to tissue damage, with a subsequent increase in liver enzyme levels in the blood of these patients.…”

Section: Discussionmentioning

confidence: 99%

The −3279C>A and −924A>G polymorphisms in the FOXP3 Gene Are Associated With Viral Load and Liver Enzyme Levels in Patients With Chronic Viral Liver Diseases

et al. 2018

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The transcription factor FOXP3 is an essential marker of the development and activation of regulatory T cells (Tregs), which are cells specialized in the regulation and normal tolerance of the immune response. In the context of chronic viral liver diseases, Tregs participate in the maintenance of infections by promoting histopathological control and favor the immune escape of viral agents by suppressing the antiviral response. Single nucleotide polymorphisms (SNPs) may influence the function of FOXP3 in a number of pathological conditions. The present study sought to evaluate the influence of SNPs in the FOXP3 gene promoter region in patients with chronic viral liver diseases. Three SNPs (−3279C>A, −2383C>T, and −924A>G) were analyzed in groups of patients with chronic hepatitis C (CHC), active chronic hepatitis B (CHB-A), inactive chronic hepatitis B (CHB-I), and a healthy control group (CG) using real-time PCR. The frequencies of the polymorphic variants were compared between groups and correlated with liver histopathological characteristics and enzyme levels [i.e., alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)] obtained via biopsy and from the clinical records of the participating patients, respectively. For the −2338C>T SNP, no significant differences were found in the frequencies of variants between groups or in the histological findings. Significant associations between the polymorphisms and the CHB-I group were not established. The −3279C>A SNP was associated with altered viral loads (log10) and GGT levels in CHC patients with advanced stages of inflammatory activity and liver fibrosis. The −924A>G SNP was associated with altered viral loads (log10) and liver enzyme levels among CHB-A patients with milder inflammation and fibrosis. However, the frequencies of the −3279C>A and −924A>G polymorphisms were not directly associated with the histopathological profiles of the analyzed patients. These polymorphic variants may influence hepatic function in patients with chronic viral liver diseases but are not directly associated with the establishment of the degree of inflammatory activity and liver fibrosis.

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Intrahepatic mRNA Expression of FAS, FASL, and FOXP3 Genes Is Associated with the Pathophysiology of Chronic HCV Infection

Cited by 13 publications

References 51 publications

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Involvement of the Interleukin-23/Interleukin-17 Axis in Chronic Hepatitis C Virus Infection and Its Treatment Responses

Chronic Hepatitis C: Conspectus of immunological events in the course of fibrosis evolution

The −3279C>A and −924A>G polymorphisms in the FOXP3 Gene Are Associated With Viral Load and Liver Enzyme Levels in Patients With Chronic Viral Liver Diseases

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