T helper 17 (Th17) cells are a newly identified subset of T helper cells that play important roles in host defense against extracellular bacteria as well as in the pathogenesis of autoimmune disease. The functions of Th17 cells are mediated via the production of several cytokines including interleukin (IL)-17 and IL-22. Recent studies show that the frequency of IL-17+ cells is significantly elevated in a variety of chronic liver diseases including alcoholic liver disease, viral hepatitis and hepatocellular carcinoma. IL-17 receptor is expressed virtually on all types of liver cells, while IL-22 receptor expression is restricted to epithelial cells including hepatocytes in the liver. IL-17 seems to play an important role in inducing liver inflammation via stimulating multiple types of liver nonparenchymal cells to produce proinflammatory cytokines and chemokines, while IL-22 appears to be an important factor in promoting hepatocyte survival and proliferation.
Alcohol drinking, hepatitis virus infection and nonalcoholic steatohepatitis are the three major causes of chronic liver injury and inflammation, which lead to liver fibrosis, cirrhosis and hepatocellular carcinoma.1, 2, 3, 4 Emerging evidence suggests that inflammatory responses mediated by a variety of immune cells play a key role in the development and progression of liver diseases. Among them, T cells are thought to be the main effector cells contributing to the pathogenesis of many forms of acute and chronic liver disorders. Both CD4+ and CD8+ T cells have been shown to play an important role in antiviral defenses in addition to hepatocellular damage during hepatitis viral infection,5, 6 and in the pathogenesis of autoimmune liver disease,7 alcoholic liver disease8 and hepatic ischemia/reperfusion injury.9 CD4+CD25+Foxp3+ regulatory T cells are a subset of T cells that inhibit T-cell responses, thereby generally favoring the persistence of hepatitis viral infection and tumor formation yet ameliorating T-cell-mediated hepatocellular damage.10, 11, 12, 13, 14, 15, 16, 17, 18 Recently, a new subset of T helper cells, T helper 17 (Th17), has been identified. In this review, we will summarize recent findings on the role of Th17 cells and their associated cytokines (IL-17 and IL-22) in the pathogenesis of liver diseases.
Identification of Th1 and Th2 subpopulations by Coffman and Mossman 25 years ago has allowed significant progress in understanding the role of T cells in a large spectrum of pathogenesis. However, the pathogenesis of some diseases, such as autoimmune disease, cannot be explained by this dichotomous Th1/Th2 model. Recently, a third subpopulation of T helper cells named Th17 has been described.19, 20, 21, 22 This new lineage of CD4+ T cells is involved in the pathogenesis of many autoimmune diseases and also in clearance of extracellular pathogens.19, 20, 21, 22 The differentiation of Th17 cells in mice is controlled by transforming growth factor-β, IL-6, and IL-21, while in humans the differentiation is achieved by IL-1, IL-6 and IL-23.19, 20, 21, 22 In general, murine CD4+ naive T cells can differentiate into Th17 subset within three phases. First, Th17 differentiation is initiated under stimulation with IL-6 and transforming growth factor-β. In a second step, those cells produce IL-21, which exerts a positive feedback on Th17 differentiation, allowing their amplification, and induces IL-23 receptor expression. During the third step, IL-23 cytokine that is produced by innate immune cells as well as IL-21 that is produced by T cells participate in the stabilization of Th17 phenotype. IL-6, IL-23 and IL-21 activate the signal transducer and activator of transcription-3 (STAT3), which is essential for induction of IL-22, IL-17A and IL-17F cytokines.19, 20, 21, 22 Activation of STAT3, known as a master signal in promoting Th17 inflammatory cytokine production, leads to induced expression of two transcription factors, the retinoic acid receptor-related orphan receptor gamma T (RORγt) and RORα, both are essential for Th17 development in both humans and mice.23, 24
The functions of Th17 cells are mediated via production of several cytokines including IL-22 and IL-17.19, 20, 21, 22 IL-22 mainly targets epithelial cells via binding to IL-22 receptor (IL-22R) that is restricted to epithelial cells including hepatocytes, while IL-17 targets a variety of cell types via binding to IL-17R that is expressed ubiquitously. Here we summarize the recent findings on the roles of IL-17 and IL-22 in liver injury, inflammation, regeneration in acute and chronic liver diseases.
IL-17 in liver diseases
Expression of IL-17R has been detected on all types of liver cells including hepatocytes, Kupffer cells, stellate cells, biliary epithelial cells and sinusoidal endothelial cells.25, 26, 27, 28 It has been reported that in vitro treatment with IL-17 induces expression of acute phase C-reactive protein in hepatocytes via p38 mitogen-activated protein kinase- and extracellular signal-regulated kinase 1/2-dependent nuclear factor-κB and CCAAT/enhancer-binding protein-β activation,29 and induces expression of several proinflammatory cytokines/chemokines in Kupffer cells, stellate cells and biliary epithelial cells.26, 27, 28 Such broad effects of IL-17 on multiple types of liver cells may contribute to the complex roles of IL-17 in the pathogenesis of liver diseases (Figure 1). The functions of IL-17 are mediated via binding to IL-17RA and IL-17RC,30 two isoforms of IL-17 receptor, followed by activation of a variety of signaling pathways including nuclear factor-κB and mitogen-activated protein kinases.31
Con A-induced T-cell hepatitis has been widely used to investigate the molecular mechanisms underlying T-cell-mediated liver injury.32 In this model, a single injection of Con A rapidly induces liver necrosis and inflammation with elevation of a wide variety of cytokines including Th1 (interferon (IFN)-γ), Th2 (IL-4) and Th17 (IL-17 and IL-22) cytokines. Both IFN-γ and IL-4 have been shown to play a critical role in Con A-induced liver injury and inflammation,33, 34, 35 while the role of IL-17 in T-cell hepatitis has been controversial. Zenewica et al.36 reported that after Con A injection IL-17-deficient mice had similar liver injury (elevation of serum ALT/AST) as wild-type mice while Nagata et al.37 and our group26 found that IL-17-deficient mice had slightly, yet significantly, reduced liver damage compared to wild-type mice. The discrepancy between these studies is not clear. Depletion of IFN-γ or IL-4 markedly diminished, while deletion of IL-17 only slightly reduced, Con A-induced liver injury, suggesting that both IFN-γ and IL-4 are essential while IL-17 appears to play a less important role in the pathogenesis of T-cell hepatitis. The essential role of IFN-γ and IL-4 in Con A-induced T-cell hepatitis is likely attributed to multiple detrimental functions of IFN-γ and IL-4 in the liver, including stimulation of liver inflammation and induction of hepatocyte apoptosis. Although IL-17 also targets multiple cell types in the liver to produce proinflammatory cytokines and promotes liver inflammation,26, 27, 28 IL-17 ameliorates rather than promotes hepatocyte apoptosis.26 The counteraction between proinflammatory and anti-apoptotic effects of IL-17 may contribute to the minimal effect of IL-17 on Con A-induced T-cell hepatitis.
Alcoholic liver disease
Inflammatory cell infiltration including neutrophils and T cells in the liver is known to considerably contribute to the pathologic findings prominent in alcoholic liver injury,38 although the precise mechanisms of inflammatory cell infiltration in alcoholic hepatitis remain unclear. A recent report by Lemmers et al.27 demonstrates that the IL-17 pathway may play an important role in the pathogenesis of alcoholic liver disease. Patients with alcoholic liver disease had significantly higher plasma levels of IL-17 compared with healthy subjects or patients with chronic hepatitis C virus (HCV) infection, and peripheral blood mononuclear cells from patients with alcoholic cirrhosis produced higher levels of IL-17 than those of healthy subjects. Immunohistochemistry analyses revealed that IL-17+ cells were mainly infiltrated to the fibrotic septa and inflammatory foci in chronic alcoholic liver disease. Moreover, the number of liver IL-17+ cells correlated positively with hepatocellular damage and severity of the disease in cohort study of patients with alcoholic liver disease. Double staining with fluorescently-labeled antibodies demonstrated that liver infiltrating IL-17+ cells were mainly neutrophils and T lymphocytes. Further studies suggest that IL-17 can stimulate hepatic stellate cells, which express IL-17 receptor, to produce chemokines such as IL-8 and growth-regulated oncogene-α subsequently recruiting neutrophils and thereby inducing liver inflammation in alcoholic liver disease. Although IL-17 did not induce pro-fibrotic gene expression such as α-smooth muscle actin and α1 procollagen I gene in hepatic stellate cells, the number of IL-17+ cells correlated with the liver fibrosis score and lobular inflammation in alcoholic liver disease. These findings suggest that infiltration of IL-17 secreting cells in the liver may contribute to the pathogenesis of alcoholic liver disease, and blocking or modulation of IL-17 might be a potential therapeutic strategy to treat this disease.
Chronic hepatitis B infection
Recently, two studies reported that the percentage of Th17 cells in peripheral blood was significantly increased in patients with chronic hepatitis B virus (HBV) infection and correlated positively with the severity of liver damage in these patients.39, 40 The number of CD4+IL-17+ cells in the liver was also increased in the patients with chronic HBV infection, and correlated positively with the histological activity index scores.39 In addition, Zheng et al.39 reported that serum levels of Th17-associated cytokines (IL-17 and IL-23) as well as Th1 cytokine IFN-γ were significantly elevated in patients with chronic HBV infection or HBV associated acute-on-chronic liver failure, although Ge et al40 did not find elevation of IL-17 and IFN-γ in the serum from HBV patients. Furthermore, Zheng et al.39 found that IL-17R was constitutively expressed on monocytes and myeloid dendritic cells (mDCs) in peripheral blood but was not detected on CD4+ T, CD8+ T, B and natural killer cells. The expression of IL-17R levels was slightly reduced on monocytes and mDCs from HBV patients compared with normal healthy individuals. The decreased IL-17R expression may be due to the negative feedback effects of high levels of IL-17 on the IL-17R-expressing cells. Zheng et al.39 further demonstrated that IL-17 treatment was able to activate both monocytes and mDCs and subsequently stimulate them to produce a variety of proinflammatory cytokines. In general, the ability of IL-17 to activate monocytes and mDCs was slightly reduced in patients with chronic HBV infection compared to normal healthy individuals, which is in agreement with reduced levels of IL-17R expression on their corresponding cells.39 Thus, the role of IL-17 in the pathogenesis of chronic HBV infection is likely mediated via stimulating monocytes and mDCs as well as Kupffer cells, stellate cells, and biliary epithelial cells to produce proinflammatory cytokines.
Chronic HCV infection
Several reports have shown that the frequency of IL-17+ cells was increased in the portal areas of livers from patients with chronic HCV infection.28, 41 HCV antigen-specific Th17 cells were also induced in the peripheral blood from patients with chronic HCV infection, which were suppressed by virus-induced transforming growth factor-β.42 However, the role of IL-17 in HCV infection has not been investigated. It is plausible to speculate that IL-17 may play an important role in stimulating liver inflammation during HCV infection, similar to HBV infection as mentioned above.
Autoimmune liver disease
Th17 cells are believed to play an important role in the development of a variety of autoimmune diseases, including autoimmune liver disease.43 It was reported that the frequency of IL-17+ infiltrating cells was elevated in the liver tissues from the patients with primary biliary cirrhosis.28, 41 Serum IL-17 levels and the frequency of IL-17+ cells were also found to be elevated in IL-2Rα knockout mice,41, 44 which have been identified as a murine model of primary biliary cirrhosis. The mechanisms underlying accumulation of Th17 cells and the contribution of IL-17 to the pathogenesis of primary biliary cirrhosis remain unclear. Harada et al.28 reported that treatment with poly I∶C, Pam3, or lipopolysaccharide-induced expression of Th17-inducible cytokines (such as IL-6 and IL-1β) and Th17-maintaining cytokines (such as IL-23) in cultured human biliary epithelial cells, which may be responsible for induction of Th17 cells in the liver of primary biliary cirrhosis. Human biliary epithelial cells also expressed IL-17R and produced a variety of chemokines and Th17-stimulating cytokines after stimulation with IL-17.28 It is probable that innate immune responses stimulate biliary epithelial cells to produce Th17-inducible and maintaining cytokines, which subsequently induce Th17 cell maturation. Th17 cells produce IL-17 that stimulates biliary epithelial cells to produce chemokines to induce the migration of inflammatory cells around the bile ducts that cause biliary epithelial cell damage and primary biliary cirrhosis.
Hepatocellular carcinoma (HCC)
The frequency of Th17 cells is higher in the HCC tissues than in the non-tumor tissues, which positively correlates with microvessel density in tissues and poor survival in patients with HCC.45 Further studies suggest that HCC tumor-activated monocytes produce several key proinflammatory cytokines that stimulate proliferation of functional Th17 cells within the tumor tissues.46 Despite the positive correlation of Th17 cells and poor survival in patients with HCC, the roles of these cells in HCC remain largely unknown. IL-17 has been shown to either promote tumor growth via stimulating angiogenesis or inhibit tumor growth via stimulating cytotoxic T-cell response.47 It was shown that the frequency of Th17 cells positively correlated with microvessel density in HCC tumors, suggesting that Th17 cells may promote the growth of HCC via inducing angiogenesis. In addition, Th17 cells may also promote HCC growth via production of IL-22, a cytokine has been shown to stimulate liver tumor cell proliferation.48
Other liver disorders
Elevation of IL-17 expression, which was mainly produced by γδ T cells, was found in the livers of mice infected with Listeria monocytogenes.49 IL-17-deficient mice had increased bacterial counts, liver inflammation and injury compared to wild-type mice after infection with L. monocytogenes, suggesting IL-17 plays an important role in the innate immunity against L. monocytogenes infection in the liver.49 Elevation of serum IL-17 was also reported in mice with Halothane-induced liver injury,50 patients with acute hepatitis51 and liver transplant patients with acute rejection,52 implicating a role of IL-17 in the pathogenesis of these liver disorders.
IL-22 in liver diseases
Hepatocytes, but not other types of liver cells, express high levels of IL-22R. In vitro treatment of primary hepatocytes and hepatoma cells with a low dose (10 ng/ml) of IL-22 induces STAT3 activation, and to a lesser extent STAT1 and extracellular signal-regulated kinase 1/2 activation, whereas a high dose (100 ng/ml) of IL-22 induces activation of multiple signals including STAT3, STAT1, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, p90 ribosomal S6 kinase.48, 53, 54, 55 Activation of these signaling pathways may contribute to the hepatoprotective and proliferative effect of IL-22 in the liver as discussed below.
We have previously demonstrated that treatment with IL-22 prevents, while treatment with IL-22 neutralizing antibodies enhances, Con A-induced T-cell hepatitis.48 The hepatoprotective role of IL-22 in T-cell hepatitis was also confirmed by other studies using IL-22-deficient mice36 and herpes virus entry mediator-deficient mice.56 In addition, we have also demonstrated that hydrodynamic delivery of IL-22 gene in vivo prevents liver injury induced by CCl4, Fas L and Con A.57 Although IL-22-deficient mice are more susceptible to Con A-induced liver damage, they had similar elevation of serum proinflammatory cytokines as wild-type mice after Con A injection.36 This suggests that the hepatoprotective role of IL-22 in Con A-induced T-cell hepatitis is not attributable to modulating immune responses, which is consistent with the lack of IL-22R expression on immune cells. The more inflammation in the liver observed in IL-22-deficient mice compared to wild-type mice after Con A injection is likely attributed to the enhanced necrosis in the former group as necrosis is associated with inflammation. Moreover, overexpression of IL-22 in human hepatoma HepG2 and Hep3B cells markedly diminished serum-starvation-induced cell death, which is associated with activation of STAT3 and induction of the STAT3-downstream anti-apopotic genes including Bcl-xL, Bcl-2 and Mcl-1.48 Collectively, the protective effect of IL-22 in Con A-induced T-cell hepatitis is likely mediated via direct hepatoprotection of IL-22 activation of STAT3 and its downstream anti-apoptotic genes, thereby reducing hepatocyte apoptosis/necrosis and associated liver inflammation.
In vitro treatment with IL-22 stimulates proliferation of primary hepatoctyes and hepatoma cells,48, 55 suggesting that IL-22 may have a role in stimulating liver regeneration. However, serum and hepatic IL-22 levels were not significantly elevated in most of liver injury models including 2/3 partial hepatectomy, a model widely used to study liver regeneration. Thus, IL-22 may not play an important role in liver regeneration in these models. Interestingly, a recent study showed that expression of IL-22R not IL-22 was elevated in the liver after partial hepatectomy, and treatment with IL-22 neutralizing antibody reduced liver regeneration,58 suggesting that IL-22 may have a role in stimulating liver regeneration in this model. Since IL-22 is significantly elevated in Con A-induced T-cell hepatitis,26, 48 it is probable that IL-22 not only plays a key role in ameliorating hepatocellular damage but also in stimulating liver regeneration in this model.
Elevation of IL-22 mRNA was detected in the livers from patients with chronic HCV infection as well as HBV infection, autoimmune hepatitis, or hepatitis of unknown origin, while serum levels of IL-22 was not elevated in these patients.55, 59 In vitro treatment with IL-22 did not induce expression of antiviral proteins in hepatocytes and had no effect on HCV infection,59 suggesting IL-22 does not have antiviral activity. At the present, the role of IL-22 in hepatitis viral infection remains unknown. Since IL-22 has been shown to protect against hepatocyte death, it is plausible to speculate that elevated IL-22 may protect against hepatocyte damage during HCV infection.
In summary, the frequency of Th17 cells is elevated in the liver and serum from the patients with various forms of acute and chronic liver injury. The hallmark of Th17 cells is the production of IL-17, which stimulates virtually all types of liver nonparenchymal cells as well as monocytes/mDC to produce proinflammatory cytokines and chemokines to induce liver inflammation (Figure 1). IL-17 can also target hepatocytes and promote hepatocyte survival. Another hallmark of Th17 cells is the production of IL-22. However, Th17-mediated production of IL-22 has not been thoroughly investigated in liver diseases mentioned above. Zhang et al.39 found that peripheral Th17 cells from patients with chronic HBV infection had little capacity to produce IL-22, which is consistent with unchanged serum levels of IL-22 in these patients. Since IL-22 mRNA expression was elevated in the livers from patients with various forms of liver diseases,55, 59 it is of great interest to determine whether hepatic Th17 cells have the ability to produce IL-22. By using in vivo animal models and in vitro cell culture models, we and others have clearly demonstrated that IL-22 is an important factor preventing hepatocyte death and promoting hepatocyte survival,36, 48, 56, 57 implicating therapeutic potential of IL-22 in treating acute liver injury.
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This work was supported by the intramural program of NIAAA, NIH.
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Lafdil, F., Miller, A., Ki, S. et al. Th17 cells and their associated cytokines in liver diseases. Cell Mol Immunol 7, 250–254 (2010). https://doi.org/10.1038/cmi.2010.5
- alcoholic liver disease
- liver cancer
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