Serum IL-33 Levels Are Associated with Liver Damage in Patients with Chronic Hepatitis C

Department of Central Laboratory, The Second Part of First Hospital, Jilin University, Changchun 130032, China.
Mediators of Inflammation (Impact Factor: 3.24). 01/2012; 2012:819636. DOI: 10.1155/2012/819636
Source: PubMed


Interleukin-33 (IL-33) is associated with the development of Th2 responses. This study examined the potential role of IL-33 in the pathogenic process of chronic hepatitis C (CHC) in Chinese patients. The levels of serum IL-33 and sST2 in 154 patients with CHC, 24 with spontaneously resolved HCV (SR-HCV) infection and 20 healthy controls (HC), were analyzed by ELISA. The concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, and IL-10, HCV loads, ALT, AST, and HCV-Ab were measured. We found that the levels of serum IL-33 in CHC patients were significantly higher than those of SR-HCV and HC but decreased after treatment with interferon for 12 weeks. More importantly, the levels of serum IL-33 were correlated with the concentrations of ALT and AST in CHC patients. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHC and SR-CHC patients than those in HC, and there was no correlation between the levels of serum sST2 and IL-33. The concentrations of serum IFN-γ and IL-6 in CHC patients were significantly lower than those of SR-HCV. These data suggest that IL-33 may be a pathogenic factor contributing to CHC-related liver injury.

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Available from: Yanfang Jiang, Oct 13, 2015
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    • "The over-expression of IL-33 and ST2 is associated with acute and chronic liver diseases in mice and human. IL-33 and sST2 have shown to be up-regulated in acute on chronic and chronic hepatic failure [15] and in chronic HBV and HCV infections in human [14,16,17]. The cellular sources of IL-33 in viral fulminant hepatitis are not well known. "
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    ABSTRACT: The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33.
    PLoS ONE 09/2013; 8(9):e74278. DOI:10.1371/journal.pone.0074278 · 3.23 Impact Factor
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    ABSTRACT: IL-33 is a novel member of the IL-1 family, which has been shown to play an important role in T helper 2 (Th2)-associated immune responses. Recent studies have suggested a possible role for IL-33 in the pathogenesis of liver damage during acute and chronic hepatitis; furthermore, IL-33 may be involved in the development and progression of liver fibrosis. To evaluate serum IL-33 levels in a group of patients with chronic hepatitis C (CHC) genotype 1b at enrolment and after a course of pegylated (PEG)-IFN plus ribavirin. 60 patients with chronic hepatitis C (CHC) and 65 healthy controls were examined and compared for serum IL-33 levels by ELISA. All CHC patients were submitted to liver biopsy either before starting antiviral treatment or during post-treatment follow up. We evaluated whether post-treatment IL-33 concentration was associated with histologic outcome as well as with virologic response to therapy. Serum IL-33 levels were significantly higher among CHC patients in comparison with healthy controls. IL-33 concentration was lower among patients with a METAVIR fibrosis score F1-F2, compared with those having a more advanced liver disease (METAVIR stage F3-F4). In addition, sustained virologic response (SVR) was associated with a significant drop in IL-33 levels, whereas no changes were found among relapsers and nonresponders. Analogously, patients experiencing liver histologic improvement after antiviral therapy had lower post-treatment IL-33 levels in comparison with baseline values. Contrarily, no variations were detected among subjects with worsened or stable histologic features. IL-33 may represent a new and easy-to-detect biomarker for the diagnosis of liver damage in CHC patients, as it appears to be modulated in parallel with biochemical and histologic parameters, such as ALT levels and liver fibrosis. Furthermore, considering that serum IL-33 concentration was significantly reduced following a successful course of antiviral treatment, this cytokine may also represent a sensitive indicator of SVR.
    Hepatitis Monthly 12/2012; 12(12):e7611. DOI:10.5812/hepatmon.7611 · 1.93 Impact Factor
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    ABSTRACT: Molecules containing damage-associated molecular patterns play an important role in many pathogenic processes. In this study, our aim was to investigate the role of IL-33, a damage-associated molecular pattern molecule, in adenovirus (Ad)-induced liver inflammation. Ad-infected mice exhibited a steadily increased IL-33 and its receptor IL-1R-like 1 expression in the liver during the first week of infection. Treatment of exogenous IL-33 resulted in a great decrease in the serum alanine aminotransferase levels and the number of Councilman bodies in the liver. Attenuated liver injury by IL-33 correlated with an increase in T regulatory cells but with a decrease in macrophages, dendritic cells, and NK cells in the liver. IL-33 enhanced both type 1 (IL-2 and IFN-γ) and type 2 (IL-5 and IL-13) immune responses in infected mice. However, IL-33 inhibited TNF-α expression in hepatic T cells and macrophages, and significantly reduced TNF-α levels in the liver. We found that in addition to its direct effects, IL-33 strongly induced novel nuocytes in the livers and spleens of infected mice. When cocultured with nuocytes, hepatic T cells and macrophages expressed lower levels of TNF-α. The IL-33-treated mice also demonstrated a slight delay, but no significant impairment, in eliminating an intrahepatic infection with Ad. In conclusion, this study reveals that IL-33 acts as a potent immune stimulator and a hepatoprotective cytokine in acute viral hepatitis. Its direct immunoregulatory functions and ability to induce novel nuocytes further suggest to us that it may be a potentially promising therapeutic candidate for the management of viral hepatitis.
    The Journal of Immunology 04/2013; 190(11). DOI:10.4049/jimmunol.1300117 · 4.92 Impact Factor
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