Immune-mediated liver injury is the key feature of hepatitis B pathogenesis. Recently, much attention has been paid to the importance of Treg cells in chronic HBV infection [
21]. In the study described herein, we investigated the expression levels of Foxp3 (the cell-specific transcription factor of Treg cells) and IL-23/IL-17 pathway-related cytokines in HBV-infected liver tissue. We found that Foxp3 and IL-23/IL-17 pathway-related cytokines were significantly higher at sites of inflammation. Moreover, the expression of Foxp3 was closely correlated with the presence of IL-23/IL-17 pathway-related cytokines.
The inflammatory response is necessary to clearance of pathogenic agents, but a fine balance must be maintained so that chronic inflammation does not damage healthy tissues. Treg cells that express Foxp3 play a key role in regulating this delicate equilibrium [
22]. Several studies of HBV infection have found that Treg cells are functionally involved in the hepatic immunological responses [
6‐
10]. Likewise, we also observed Foxp3 expression in CD4
+ T cells, and not in CD8
+ T cells. Moreover, the expression of Foxp3 was significantly increased and in liver tissue of CHB patients. Moreover the mRNA level of Foxp3 at sites of hepatic inflammation was closely correlated with levels of HBV DNA copies and HBsAg. These results indicated that Foxp3 expression was likely to support established residence of HBV.
Recently, clinical investigations have shown that the IL-23/IL-17 signaling pathway contributes to the inflammatory reaction of Crohn's disease, psoriasis and systemic lupus erythematosus [
18,
23,
24]. IL-17 is known as the immune-modulatory factor of Th17 cells, while IL-23 functions to elicit the differentiation and mediate the function of Th17 cells [
25]. Several groups have reported that the IL-17 pathway was involved in human liver disease [
13,
14,
26,
27]. Our results evidenced that the activity of the IL-23/IL-17 pathway was significantly elevated in liver tissues of patients infected by hepatitis B virus, as compared to that in healthy controls. These results indicated that the IL-23/IL-17 pathway, rather than IL-17 alone, is involved in the pathological process of hepatitis B infection.
Th17 cells and Treg cells both arise from the naive CD4
+ T cell population and share reciprocal development pathways. But, they have opposite immunomodulatory effects, and the balance between them controls inflammation and autoimmune diseases [
28]. Many studies have identified an imbalance in Th17 cells and Treg cells that occurs in conjunction with disease [
6,
29‐
31]. In the present study, we found that expression of Foxp3 and IL-23/IL-17 pathway-related cytokines were increased in inflamed hepatic tissues in CHB patients. We also found that Foxp3 expression was significantly correlated with levels of IL-23/IL-17 pathway-related cytokines in the livers of these CHB patients (Figure
5). Several studies have demonstrated that the development of Th17 cells and Treg cells may be interrelated, as they are both dependent on TGF-β [
32]. Yet, they appear to be reciprocally influenced by various cytokines, such as IL-6, IL-1, as well as IL-2 and the vitamin A metabolite all-
trans-retinoic acid [
33‐
35]. TGF-β is central to the development and function of Th17 and Treg cells. On one hand, TGF-β induces the expression of FoxP3 [
36]; on the other hand, TGF-β has been shown to be absolutely required for Th17 differentiation in a serum-free system using cord blood-derived CD4
+ T cells [
37]. A recent study also showed that Tregs themselves may differentiate into IL-17-producing cells, particularly when exposed to exogenous IL-1β, IL-23 or IL-21 [
38,
39]. In psoriasis patients, Zhang
et al. found that Th17 cells were positively correlated with the presence of Treg cells, both in the circulation and in skin tissue lesions [
40]. Based on these data, we propose that Tregs may act to promote the pro-inflammatory cytokines, such as IL-17 and IL-23, at certain time points during the course of HBV infection. Considering that the inflammatory response is crucial for clearance of pathogenic microorganisms, it is reasonable that the occurrence of pro-inflammatory immune cells, such as Th17, will be accompanied by inhibitory Tregs cells. In this way, the significant correlation between Treg cells and Th17 cells in the liver of CHB patients is fitting.