Association of Cytokines with Alanine Aminotransferase, Hepatitis B Virus Surface Antigen and Hepatitis B Envelope Antigen Levels in Chronic Hepatitis B

Abstract

Background:Cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to investigate the changes of cytokines concentration and its correlation to alanine aminotransferase (ALT), HBV deoxyribonucleic acid (HBV-DNA), hepatitis B envelope antigen (HBeAg), and HBV surface antigen (HBsAg) in the development of chronic hepatitis B (CHB).Methods:Thirteen healthy individuals (HI), 30 chronic HBV-infected patients in immune tolerant (IT) phase, and 55 CHB patients were enrolled between August 2015 and May 2017. The peripheral blood samples were collected from all individuals. The levels of interferon (IFN)-α2, interleukin (IL)-10, transforming growth factor (TGF)-β1, HBV-DNA, HBsAg, and HBeAg and liver function were measured. The quantitative determinations of cytokines levels, including IFN-α2, IL-10, and TGF-β1 were performed using Luminex multiplex technology. The correlation of cytokines to ALT, HBV-DNA, HBsAg, and HBeAg was analyzed by linear regression analysis.Results:IFN-α2 levels were similar between HI and IT groups (15.35 [5.70, 67.65] pg/ml vs. 15.24 [4.07, 30.73] pg/ml, Z = −0.610, P = 0.542), while it elevated significantly in CHB group (35.29 [15.94, 70.15] pg/ml vs. 15.24 [4.07, 30.73] pg/ml; Z = −2.522, P = 0.012). Compared with HI group (3.73 [2.98, 11.92] pg/ml), IL-10 concentrations in IT group (5.02 [2.98, 10.11] pg/ml), and CHB group (7.48 [3.10, 18.00] pg/ml) slightly increased (χ2= 2.015, P = 0.365), and there was no significant difference between IT and CHB group (Z = −1.419, P = 0.156). The TGF-β1 levels among HI (3.59 ± 0.20 pg/ml), IT (3.62 ± 0.55 pg/ml), and CHB groups (3.64 ± 0.30 pg/ml) were similar (χ2= 2.739, P = 0.254). In all chronic HBV-infected patients (including patients in IT and CHB groups), the elevation of IFN-α2 level was significantly associated with ALT level (β= 0.389, t = 2.423, P = 0.018), and was also negatively correlated to HBV-DNA load (β = −0.358, t = −2.308, P = 0.024), HBsAg (β = −0.359, t = −2.288, P = 0.025), and HBeAg contents (β = −0.355, t = −2.258, P = 0.027). However, when both ALT level and cytokines were included as independent variable, HBV-DNA load, HBsAg, and HBeAg contents were only correlated to ALT level (β = −0.459, t = −4.225, P = 0.000; β = −0.616, t = −6.334, P = 0.000; and β = −0.290, t = −2.433, P = 0.018; respectively).Conclusions:IFN-α2 elevation was associated with ALT level in patients with chronic HBV infection. However, in CHB patients, only ALT level was correlated to HBV-DNA, HBsAg and HBeAg contents.

Association of cytokines with hepatitis B virus and its antigen

“…IFN‐α can tot only inhibit the replication of virus directly, 12‐14 but also activate NK cells, enhance CTL to eliminate infected hepatocytes, promote the maturation of dendritic cells, stimulate CD8+ T cells, which lead to the expansion and proliferation of clones, and increase the expression of chemokines to recruit NK, T cells and B cells in the liver, activate these immune cells, thus breaking immune tolerance and activating immune response 1,15‐17 . Therefore, the increase of IFN‐α level in chronic HBV infection may be the factor that breaks immune tolerance and hepatitis occurrence 2,18 …”

“…The inflammatory cytokines are characterized by the increase of TNF‐α, IL‐10 and TGF‐β. Not only can the elevated IL‐10 inhibit the immune response and make it difficult for chronic hepatitis B to recover spontaneously, but also it can avoid excessive liver tissue injury and endanger the lives of patients 2 …”

“…The level of HBeAg was also positively correlated with the level of IFN‐γ and IL‐17A. Flt‐3L, IFN‐α, IFN‐γ and IL‐17A are the cytokines with significant viral clearance and immunostimulatory function 2,25 . In the chronic development of HBV infection, the deficiency of pDC function is a of crucial importance.…”

“…The occurrence, degree and prognosis of hepatitis after HBV infection depends on the environment composed of the immune cells of the patients and their corresponding cytokines. Immunity and virus determine the prognosis of patients with HBV infection 2,3 . The occurrence of chronic hepatitis B is a result of interaction between virus and its stimulated immunity.…”

Research progress in host immune response during hepatitis B virus infection

“…[ 7 ] IFN-α, an important cytokine with immune stimulation action, is mainly secreted by pDC, were elevated significantly in CHB patients when compared to patients in IT phase. [ 8 ]…”