Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: a proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10.

Soriane De Souza-Cruz,Olindo Assis Martins-Filho,Adriana Malheiro,Lorene De Paula Araújo,Marilú Barbieri Victória,Ericka Florêncio Pires,Andréa Teixeira-Carvalho,Flamir Da Silva Victória,Andréa Monteiro Tarragô,Laurence Rodrigues Amaral,João Paulo Diniz Pimentel,Jordana Grazziela Coelho-Dos-Reis,Matheus De Souza Gomes,Allyson Guimarães Da Costa

doi:10.1186/s12866-015-0610-6

Abstract

BackgroundIn this study, we have evaluated the immunological status of hepatitis C virus (HCV)-infected patients aiming at identifying putative biomarkers associated with distinct degrees of liver fibrosis. Peripheral blood and tissue T-cells as well as cytokine levels were quantified by flow cytometry.ResultsData analysis demonstrated higher frequency of circulating CD8+ T-cells and Tregs along with a mixed proinflammatory/IL-10-modulated cytokine pattern in HCV patients. Patients with severe liver fibrosis presented lower frequency of circulating CD8+ T-cells, higher levels of proinflammatory cytokines, but lower levels of IL-10, in addition to the higher viral load. Despite the lower frequency of intrahepatic T-cells and scarce frequency of Tregs, patients with severe liver fibrosis showed higher levels of proinflammatory cytokines (TNF and IFN-γ). The tissue proinflammatory cytokine pattern supported further studies of serum cytokines as relevant biomarkers associated with different liver fibrosis scores. Serum cytokine signature showed that mild liver fibrosis is associated with higher IL-10 serum levels as compared to severe liver disease. There was a clear positive connection of IL-10 with the TNF node in patients with mild liver fibrosis, whereas there is an evident inverse correlation between IL-10 with all other cytokine nodes.ConclusionsThese results suggest the absence of modulatory events in patients with severe liver damage as opposed to mild fibrosis. Machine-learning data mining pointed out TNF and IL-10 as major attributes to differentiate HCV patients from non-infected individuals with highest performance. In conclusion, our findings demonstrated that HCV infection triggers a local and systemic cytokine ensemble orchestrated by TNF and tuned by IL-10 in such a manner that mirrors the liver fibrosis score, which highly suggests the relevance of these set of biomarkers for clinical investigations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-015-0610-6) contains supplementary material, which is available to authorized users.

Highlights

In this study, we have evaluated the immunological status of hepatitis C virus (HCV)-infected patients aiming at identifying putative biomarkers associated with distinct degrees of liver fibrosis
Studies have shown that in chronic HCV infection there is a correlation between the production of proinflammatory cytokines, such as IFN-γ and tumor necrosis factor alpha (TNF-α), and progressive liver injury, while the regulatory cytokines such as IL-4 and IL-10 may modulate the proinflammatory immune response induced by the virus, allowing for the establishment of a milder disease outcome [10]
The Alanine Transaminase (ALT) data revealed that HCV patients presented high levels of this liver damage biomarker but no significant differences between patients with mild or severe liver fibrosis were observed (Fig. 1)

Summary

Introduction

We have evaluated the immunological status of hepatitis C virus (HCV)-infected patients aiming at identifying putative biomarkers associated with distinct degrees of liver fibrosis. Despite the lower frequency of intrahepatic T-cells and scarce frequency of Tregs, patients with severe liver fibrosis showed higher levels of proinflammatory cytokines (TNF and IFN-γ). Studies have shown that in chronic HCV infection there is a correlation between the production of proinflammatory cytokines, such as IFN-γ and TNF-α, and progressive liver injury, while the regulatory cytokines such as IL-4 and IL-10 may modulate the proinflammatory immune response induced by the virus, allowing for the establishment of a milder disease outcome [10]. Considering the lack of information on the local and systemic immunological biomarkers that correlate with the progression to liver fibrosis, this study aimed at investigating the balance between inflammatory and regulatory events in the peripheral blood and in the liver and their association with fibrosis score

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