The role of T helper 17 cells in the pathogenesis of hepatitis B virus-related liver cirrhosis (Review)

Abstract

In chronic hepatitis B virus (HBV)-infected patients, T helper 17 (Th17) cells are significantly elevated. Th17 cells initiate immune‑mediated pathogenesis and have a critical role in the process of HBV‑related liver cirrhosis (HBV‑LC). The mechanisms underlying this process are attributed to Th17‑secreted cytokines, which include interleukin (IL)‑17, IL‑21 and IL‑22; however, a systemic analysis regarding these mechanisms has yet to be conducted. Therefore, the present study aimed to investigate the role of Th17 cells in the pathogenesis of HBV‑LC. All randomized clinical trials, case series, case reports and meta‑analyses that contained the aforementioned keywords were included in the review process. In addition, unpublished information from the Food and Drug Administration was included. The findings indicated that Th17‑secreted cytokines, including IL‑17, IL‑21 and IL‑22, function by activating or silencing hepatic stellate cells, modulating proinflammatory and pro‑ or antifibrogenic effectors, regulating extracellular matrix formation, upregulating chemokine expression, and inducing hepatocellular damage or hepatoprotection during the HBV‑LC process. In addition, Th17 cells and Th17‑secreted cytokines may be considered a potential tool in the diagnosis or treatment of HBV‑LC. The present review summarized the role of Th17 cells in the pathogenesis of HBV‑LC in order to deepen the clinical understanding of the role of Th17 cells and also to support the development of effective therapies for patients with HBV‑LC.

Figure 1.

IL-17 and IL-21 serve similar roles in modulating liver cirrhosis. IL-17 promotes liver fibrosis by inducing HSC and KC activation, subsequently resulting in the upregulation of chemokines (IL-8, GRO-α) in HSCs, and fibrogenic (α-SMA, collagen) and proinflammatory genes (TGF-β, IL-6, TNF-α) in HSCs and KCs. In addition, IL-21, which is produced by Th17 cells, induces HSC activation, resulting in the production of fibrogenic genes (α-SMA, collagen), which promotes the development of liver fibrosis. IL, interleukin; GRO-α, growth related oncogene-α; HSC, hepatic stellate cell; KC, Kupffer cell; Th17, T helper 17 cells; α-SMA, α-smooth muscle actin; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.

Figure 2.

IL-22 serves a dual role in the process of liver cirrhosis. In chronic or HBV Tg-induced liver cirrhosis, IL-22 promotes liver cirrhosis by activating HSCs, which upregulates chemokines (CXCL10, CXCL20) and fibrogenic genes (α-SMA, collagen) or promotes hepatocellular damage. Conversely, in acute, or CCL₄- and BDL-induced liver cirrhosis, IL-22 induces the expression of SOCS3, p53 and p21 in HSCs, which contributes to IL-22-mediated HSC senescence, subsequently downregulating fibrogenic (α-SMA, collagen) and proinflammatory genes (TGF-β, IL-6, TNF-α), and thus protecting against hepatocellular damage. IL, interleukin; HBV, hepatitis B virus; Tg, transgenic; HSCs, hepatic stellate cells; Th17, T helper 17 cells; CXCL10, chemokine (C-X-C motif) ligand 10; CXCL20, chemokine (C-C motif) ligand 20; α-SMA, α-smooth muscle actin; CCL₄, carbon tetrachloride; BDL, bile duct ligation; TGF-β, transforming growth factor-β; SOCS3, suppressor of cytokine signaling 3; LC, liver cirrhosis; TNF-α, tumor necrosis factor-α.