In this study, we demonstrated that serum IL-17 protein levels and PBMC IL-17A mRNA levels were found to be significantly higher in HBV-infected patients when compared to normal controls. IL-17 expression in the liver tissues of the patients was positively correlated with inflammation grade and fibrosis stage, and positively stained lymphocytes suggested that IL-17 takes part in chronic HBV infection. The highest IL-17 levels in the serum and liver were observed in LC patients, suggesting that IL-17 might contribute to the pathogenesis and/or progression of liver fibrosis. Therefore, IL-17 represents a potential therapeutic target for the prevention of liver tissue damage in HBV-infected patients.
Because of the inflammatory reaction of the hepatic tissues in CHB, activated interstitial cells can produce large amounts of TGF-β. TGF-β plays an important role in the differentiation of IL-17. TGF-β together with IL-6 can mediate the de novo differentiation of IL-17-producing T cells from naive CD4+ T cell precursors . Th17 is a recently described CD4+ helper T cell subset that produces pro-inflammatory mediators IL-17 and IL-6, which can exacerbate liver damage during chronic HBV infection. One study has also found that peripheral Th17 cells from CHB patients have little capacity to produce IL-22, a cytokine which has been demonstrated to protect against T-cell-mediated hepatitis. The loss of TH17- cells producing IL-22 might exacerbate liver injury in CHB patients [22, 23]. IL-17R is expressed in a variety of cell types, which bind the proinflammatory mediator IL-17, and can induce NF-kB activity, improve the induction of NF-kB DNA binding activity, and promote the production of a variety of proinflammatory cytokines by different cell types [9, 10]. IL-17 acts synergistically with other pro-inflammatory cytokines in the amplification of the inflammatory response .
In the current study, we also found that the serum IL-17 protein levels, PBMC IL-17A mRNA levels, and IL-17 gene expression in the liver were all higher in the patients with LC. IL-17 expression was mainly localized in the portal area and positively correlated with the serum hepatic fibrosis indices (r = 0.692, P < 0.01), which were closely correlated with fibrosis in the liver. We also found that fibroblasts in the liver were positively stained. Liver fibrosis is an important pathological process in the development of liver cirrhosis, which suggests that IL-17 might play an important role in the fibrogenesis and progression of chronic hepatitis B. Some reports have demonstrated that the cytokines TGF-β, interleukin-6, interleukin-1, and TNF-α play important parts in the pathogenesis of liver fibrosis and cirrhosis in CHB [12, 13]. IL-17 is biologically closely correlated with some cytokines. TGF-β, together with DC-derived IL-6, is essential for de novo differentiation of IL-17-producing T cells from naive CD4 T cells in vitro, a process that is amplified by IL-1β and TNFα . Th17 has been shown to induce the secretion of IL-6.
Hepatic stellate cell activation remains the major step in the pathway of fibrogenesis within the liver when inflammation is present. There is some evidence that the activation of the quiescent hepatic stellate cells into an activated myofibroblast phenotype results in the production of fibrillar collagen [24, 25]. IL-17 has been found to be highly expressed in many fibrotic-diseases. Whether the effect of IL-17 in the fibrotic process is related with the stellate cell requires further investigation. In our study, we found IL-17 level positively related with the liver fibrosis, the higher fibrosis grade, the higher IL-17 level, but no correlation with PHC and HCC.
In the current study, we found that the serum IL-17 protein levels and the PBMC IL17A mRNA levels were high in the patients with PHC, which suggested that IL-17 takes part in the pathogenesis of PHC. One previous study showed that IL-17 had significant tumor-promoting effects via potentiation of tumor angiogenesis . Another study showed that IL-17 can inhibit the pathogenesis of tumors via an immune-mediated tumor rejection. Therefore, IL-17, like other cytokines, appears to be a pleiotropic cytokine with possible protumor or antitumor effects, in which the predominant effect often depends on the immunogenicity of the tumors . The relationship between IL-17, microvessel density of hepatocellular carcinoma, and the effect of IL-17 in the pathogenesis of the PHC requires further investigation.
The serum IL-17 protein levels and the IL-17 expression in the liver tissue were negatively correlated with albumin levels, and the ratio of albumin to globulin suggested that IL-17 is, to a certain extent, positively correlated with liver damage. ALT can be easily affected by drugs which decrease the enzyme, which may explain why the hepatic histological inflammation grades in some of the patients were not positively correlated with the ALT. The measurement of prothrombin activity is affected by the normal control serum. HBV can induce inflammation of the liver by stimulating the immune system without directly inducing the pathological changes of the hepatic cell. We suspect that this might explain the finding of a lack of relationship between the serum ALT, PTA, HBVDNA concentrations, and the IL-17 in the current study.
Taken together, we have demonstrated that the higher the degree of liver fibrosis, the higher the levels of IL-17 expression. This suggests that IL-17 perhaps may prompt stellate cell and fibroblast proliferation, which may determine the degree of fibrosis. It may also be a valuable indicator for disease progression and prognosis. Increased expression of IL-17 in HBV infected patients also supports a role for IL-17 in the infection, but the exact mechanism of action needs further investigation.