Arch Virol DOI 10.1007/s00705-014-2002-x
BRIEF REVIEW
IL-17A in hepatitis B infection: friend or foe? Mohammad Kazemi Arababadi • Mohammad Zare Bidaki Derek Kennedy
•
Received: 9 September 2013 / Accepted: 21 January 2014 Ó Springer-Verlag Wien 2014
Abstract Hepatitis B virus (HBV) is one of the most prevalent and infectious agents that leads to liver disease in humans. Five clinical forms of HBV infection exist, including fulminant, acute, chronic, asymptomatic and occult. The chronic, asymptomatic and occult forms are long-term infections that can lead to hepatocellular carcinoma (HCC) and liver cirrhosis. The mechanisms responsible for progression of these forms of the infection to HCC and liver cirrhosis are not yet clearly understood or characterised. However, genetic and immunological parameters may play important roles in the disease. IL-17A is an important cytokine involved in early immune responses against fungal and bacterial infections, but its role in the response against viral infections is yet to be fully clarified. The crucial roles of IL-17A in the pathogenesis of autoimmune and destructive immune-related diseases have been documented and may provide insights into its functions during hepatitis infection. Therefore, the aim of this review was to address the recent information regarding the status and association of IL-17A during hepatitis B infection and its related disorders, including HCC and liver cirrhosis.
M. K. Arababadi M. Z. Bidaki Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran D. Kennedy (&) School of Biomolecular and Physical Science, Eskitis Institute for Drug Discovery, Griffith University Nathan, Queensland, Australia e-mail: [email protected]
Introduction Hepatitis B virus (HBV) is the most prevalent and dangerous infectious agent that leads to hepatic disease in humans [4]. The major clinical presentations of hepatitis are related to immune system responses against infected hepatocytes [5]. Based on variations in the efficacy of immune responses against HBV, five forms of the disease are possible, and these include fulminant, acute, chronic, asymptomatic and occult HBV infection [5]. Furthermore, previous studies have revealed that hepatocellular carcinoma (HCC) and liver cirrhosis can develop following the chronic, asymptomatic and occult forms of hepatitis B [7]. The mechanisms responsible for the progression of prolonged infection to the onset of HCC or cirrhosis are yet to be fully clarified. However, some scientists have suggested that genetic and immunological parameters may play crucial roles in the pathogenesis of hepatitis B [2, 26]. Recent studies have demonstrated that cytokines play an important role in the induction of an appropriate immune response to eradicate the viral infection and in the incidence of liver cirrhosis or HCC in HBV-infected patients [13, 24, 34]. IL17A is a proinflammatory cytokine with dual effects in immune responses, which include the early beneficial responses against infections and the detrimental effects associated with autoimmunity and inflammatory diseases [3]. Previous studies showed that IL-17A is essential for initiating and sustaining suitable immune responses against fungal and bacterial infections [25], while its role against viral infections is yet to be clarified. Immune responses to HBV play dual roles in combating HBV infection [2] as well as the destruction of hepatocytes and induction of cirrhosis and HCC [14], and based on the fact that IL-17A plays dual roles in immune responses [11], this review compiles recent information regarding the relationship
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Fig. 1 Cytokines driving T helper cell differentiation. The diagram illustrates the cytokines required for differentiation from naı¨ve T cells (Th0) to Th1, Th2 or TH17 helper cells. IL-1b, IL-6, IL-21 and TGFb are required for Th0 cell differentiation into Th17 helper cells
Fig. 2 The positive feedback between Th17 and innate immune cells. The figure highlights the pathway, showing Th17 in a positive feedback loop that induces macrophages (MU) and dendritic cells (DC) to produce IL-1b, IL-6 and TGF-b via IL-17A
and IL-12 are the main cytokines that induce the Th1 subtype, while, IL-4 leads to Th2 differentiation [43]. It has also been documented that IL-6 in parallel with TGF-b and IL-1b induce Th17 differentiation, and IL-23 is important for cell maintenance (Fig. 1) [43]. IL-21 also leads to Th17 lineage development in an autocrine manner [32]. Several cytokines have been implicated in Th17 development, and these increase expression of two transcription factors, RORct and RORa, which induce Th17 differentiation [17]. The transcription factors are also responsible for expression of Th17-related genes, including IL-21, IL-22, IL-26, IL17A and F [17]. Interestingly, Th17 has a positive feedback on innate immunity because IL-6 and IL-1b, which are also inducers of Th17 differentiation and its downstream IL17A production, give rise to the development of innate immune cells, including macrophages and dendritic cells, which in turn produce IL-6 and IL-1b (Fig. 2) [12].
Introducing IL-17A IL-17A is a homodimeric 35-kDa protein containing 123 amino acids [16]. IL-17A induces its signal to target cells via IL-17R (a type I cell-surface receptor), which has three variants, including IL17RA, IL17RB, and IL17RC [27]. IL-17A plays dual roles in immune responses against infection. The first role provides a benefit to the host combating infection [20]; however, it is also implicated in detrimental effects such as autoimmunity and immunerelated disorders [21]. Although IL-17A participates in immune responses against fungal and bacterial infections, there is a limited amount of data regarding the role of this cytokine in immune responses against HBV. The association of IL-17A with immune-related diseases, including inflammatory conditions, has led to the hypothesis that this cytokine may contribute to the pathogenesis of HBV infection, including cirrhosis and HCC.
IL-17A and HBV infection between IL-17A and its main source, Th17 cells, to HBV infection. The review also addresses the current data regarding the roles of IL-17A in the pathogenesis of liver cirrhosis and HCC.
Differentiation of Th17 cells In vivo and in vitro studies have demonstrated that all T helper lymphocytes are derived from naı¨ve T lymphocytes and that the developmental history, exposure to cytokines, and microenvironment of the cell determine what kind of T helper cell will be produced from the precursor [42]. IFN-c
123
As mentioned in the introduction, HBV and immune system responses against infected hepatocytes are responsible for the major clinical presentations of hepatitis, including HCC and liver cirrhosis [5], but a complete and specific immune response against HBV can lead to the eradication of the virus [6] and reduce the risk of subsequent disease. Accordingly, some studies have evaluated the roles and status of IL-17A during various forms of hepatitis B. Gehring et al., demonstrated that, during acute infection, HBV-specific T cells were unable to produce IL-17A in response to infected hepatocytes, suggesting that the inflammation within the liver during these phases of HBV
IL-17A in hepatitis B
infection is not directly related to IL-17A and may be due to the expression of other cytokines [9]. Considering that a major and powerful immune response is induced during acute hepatitis B infections, it may be concluded that IL17A is not important in the development of appropriate immune responses against HBV. However, in contrast to responses to acute HBV infection, several studies have demonstrated that IL-17A is upregulated during chronic hepatitis B infections, especially in patients with liver cirrhosis and HCC. Therefore, it appears that this cytokine could be considered a risk factor for liver complications. For instance, Zhang et al. revealed that, in parallel with IL6R?/CD4? T cell elevation, Th17 responses are also increased in chronically HBV-infected patients [38]. Furthermore, it has been established that IL-6 is increased in parallel to liver injury; hence, it could be concluded that Th17 is one of the main cell types implicated or associated with the pathogenesis of chronic HBV infection. Wang et al. showed that there is an increase in T regulatory lymphocytes in chronically HBV-infected patients [31] and that elevated T regulatory cells is associated with immune suppression and long-term HBV infection. Interestingly, these authors showed that the IL-23/IL-17 pathway-related proinflammatory cytokines were also significantly increased in the patients [31]. Therefore, it seems that T regulatory cells are unable to control Th17 function and that liver pathology can be affected by this pathway. Zhang et al. also demonstrated that, in patients undergoing entecavir treatment, the numbers of HBV-DNA particles and T regulatory cells were decreased, and this was accompanied by a rapid increase in the number of Th17 cells [39]. Interestingly, they also revealed that, although the numbers of Th17 cells were increased, their ability to produce IL17A was decreased [39]. Therefore, it seems that therapy with antiviral drugs can inhibit Th17 function and may result in reduced liver injury. Ye et al. reported that the number of Th17 cells found in livers of chronically HBVinfected patients with severe hepatocellular damage was significantly increased when compared to Th1 cells [36], and these results were also confirmed by Zhang et al., who reported that the number of Th17 cells increased with the severity of liver damage in chronic hepatitis B patients [40]. Furthermore, Chinese researchers reported that increased numbers of Th17 cells are positively associated with elevated serum levels of ALT during severe chronic HBV infection [33]. The negative and positive correlation between Th17 and Th1 cells and ALT, respectively, in chronically HBV-infected patents were reported by Ge and colleagues [8]. Additionally, Xu et al., also found that serum levels of IL-17A are significantly increased in HBVrelated liver diseases, especially in hepatitis-B-related liver cirrhosis [35]. Wang et al. showed that the expression of IL-17A in chronically HBV-infected patients, especially in
liver fibrosis, was significantly increased in comparison to healthy controls [30]. Interestingly, they reported that the levels of IL-17A are strongly correlated with the degree of fibrosis [30]. Sun and colleagues demonstrated that increased levels of Th17 cells are significantly associated with disease progression in patients with HBV-associated liver cirrhosis [28]. Another study on the Chinese population revealed that the Th17:T regulatory cell ratio is an important marker for the diagnosis of liver injury and that an increased ratio is related to the deterioration of liver fibrosis [22]. These results were confirmed by Li et al., and their study showed that an increased Th17:T regulatory cell ratio is indicative of more-severe liver injury and fibrosis [19]. Zhai et al. also reported that the Th17:Treg cell ratio was associated negatively with the survival of HBV-associated acute-on-chronic liver failure patients [37]. Recently, Qi et al. reported that patients with liver failure carried more peripheral Th17 cells in comparison to chronically HBV-infected patients and controls [23]. In addition to studies on acute and chronic infection, previous studies demonstrated that occult HBV-infected patients are also at risk of liver cirrhosis and HCC development [7]. Our previous studies revealed that serum levels of IL-17A are significantly increased in occult HBV-infected patients [1]. Overall, the data presented suggest that Th17 cells and/ or the expression of IL-17A play an important role in the pathogenesis of liver injury in all of the clinical forms of HBV infection. It seems that IL-17A may be involved in several mechanisms that promote HCC in HBV-infected patients. For example, Gu et al. proposed that IL-17A promotes HCC development through AKT, which activates the IL6/JAK2/STAT3 pathway [10] (see Fig. 3). In addition, it has been established that IL-17A expression was significantly and positively associated with STAT3 phosphorylation and elevated tumor vascularity [10]. Furthermore, IL-17A induces its signal to target cells via the STAT3 pathway [32], and accordingly, it was shown that STAT3 knockout mice had no susceptibility to viral infections. Interestingly, type I IFNs, which are among the first immune responses against viral infections, suppress Th17 differentiation and IL-17A expression under in vitro and in vivo conditions [29]. Zhao et al. suggested that IL-17A suppresses T cytotoxic lymphocyte functions by inducing B7-H1(?) macrophages (Mphis) [41]. T cytotoxic lymphocytes are the main adaptive immune responses against tumors. Therefore the decrease in these cells and the complimentary increase in B7-H1(?) macrophages swings the course of the disease towards tumorigenesis. The progression of tumourigenesis is enhanced by IL-17A activation of the NF-kB signaling pathway and subsequent increased expression of MMP2 and MMP9, which are
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M. K. Arababadi et al. Fig. 3 IL-17 promotes HCC development through the AKT pathway and the subsequent increased expression of IL-6, MMP9 and MMP2. IL-6 induces immune cells to express MMP2, VEGF and IL-8. MMP molecules enhance metastasis, while VEGF leads to increased angiogenesis. IL-17 also activates STAT3, MAPK/ ESRK, CJNK and C-FOS signaling pathways via activation of TPL2, which leads to elevation of AP-1 transcription and phosphorylation. Additionally, IL-17 suppresses T cytotoxic lymphocyte functions by inducing B7-H1(?) macrophages
two important factors in the induction of HCC metastasis [18]. Supportive evidence for this model was revealed when Th17 cells were detected in HCCs with metastasis and it was shown that their frequency was also significantly associated with poor prognosis of HCC [18]. IL17A is also able to promote neoplastic transformation in JB6 Cl41 cells through activation of tumor progression locus 2 (TPL2) (Fig. 3) [15].
Conclusion Collectively, it appears that the roles of IL-17A in the induction of appropriate immune responses against viral infections are controversial, and more studies are needed to improve our knowledge. However, the published data regarding Th17 and hepatitis B infection, suggest that IL-17A may play an important role in the development of HBV-related liver diseases, especially the pathophysiology of hepatitis-B-related liver fibrosis, cirrhosis and HCC, and future therapies could be directed towards the control of Th17 functions as an
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intervention to prevent liver injury. Additionally, it has been established that the immune system is suppressed during chronic HBV infection and that the number of T regulatory lymphocytes is increased in these patients, while the number of Th17 cells is increased during liver failure in these patients. Therefore, it is likely that Th17 cell functions are not directly under the control of T regulatory cells and that additional mechanisms are involved in the regulation of Th17 function. There is an urgent need for future studies in this field to improve our knowledge regarding the mechanisms involved in the regulation of Th17 function. Research directed at understanding these control mechanisms may shed light on strategies that can be implemented for the treatment of long-term HBV infections and the control of HBVrelated liver damage. Acknowledgements This project was supported by a grant from the Rafsanjan University of Medical Sciences. None of the authors have any financial, professional or personal conflicts that are relevant to the manuscript. Conflict of interest exist.
The authors declare that no competing interests
IL-17A in hepatitis B
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BRIEF REVIEW
IL-17A in hepatitis B infection: friend or foe? Mohammad Kazemi Arababadi • Mohammad Zare Bidaki Derek Kennedy
•
Received: 9 September 2013 / Accepted: 21 January 2014 Ó Springer-Verlag Wien 2014
Abstract Hepatitis B virus (HBV) is one of the most prevalent and infectious agents that leads to liver disease in humans. Five clinical forms of HBV infection exist, including fulminant, acute, chronic, asymptomatic and occult. The chronic, asymptomatic and occult forms are long-term infections that can lead to hepatocellular carcinoma (HCC) and liver cirrhosis. The mechanisms responsible for progression of these forms of the infection to HCC and liver cirrhosis are not yet clearly understood or characterised. However, genetic and immunological parameters may play important roles in the disease. IL-17A is an important cytokine involved in early immune responses against fungal and bacterial infections, but its role in the response against viral infections is yet to be fully clarified. The crucial roles of IL-17A in the pathogenesis of autoimmune and destructive immune-related diseases have been documented and may provide insights into its functions during hepatitis infection. Therefore, the aim of this review was to address the recent information regarding the status and association of IL-17A during hepatitis B infection and its related disorders, including HCC and liver cirrhosis.
M. K. Arababadi M. Z. Bidaki Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran D. Kennedy (&) School of Biomolecular and Physical Science, Eskitis Institute for Drug Discovery, Griffith University Nathan, Queensland, Australia e-mail: [email protected]
Introduction Hepatitis B virus (HBV) is the most prevalent and dangerous infectious agent that leads to hepatic disease in humans [4]. The major clinical presentations of hepatitis are related to immune system responses against infected hepatocytes [5]. Based on variations in the efficacy of immune responses against HBV, five forms of the disease are possible, and these include fulminant, acute, chronic, asymptomatic and occult HBV infection [5]. Furthermore, previous studies have revealed that hepatocellular carcinoma (HCC) and liver cirrhosis can develop following the chronic, asymptomatic and occult forms of hepatitis B [7]. The mechanisms responsible for the progression of prolonged infection to the onset of HCC or cirrhosis are yet to be fully clarified. However, some scientists have suggested that genetic and immunological parameters may play crucial roles in the pathogenesis of hepatitis B [2, 26]. Recent studies have demonstrated that cytokines play an important role in the induction of an appropriate immune response to eradicate the viral infection and in the incidence of liver cirrhosis or HCC in HBV-infected patients [13, 24, 34]. IL17A is a proinflammatory cytokine with dual effects in immune responses, which include the early beneficial responses against infections and the detrimental effects associated with autoimmunity and inflammatory diseases [3]. Previous studies showed that IL-17A is essential for initiating and sustaining suitable immune responses against fungal and bacterial infections [25], while its role against viral infections is yet to be clarified. Immune responses to HBV play dual roles in combating HBV infection [2] as well as the destruction of hepatocytes and induction of cirrhosis and HCC [14], and based on the fact that IL-17A plays dual roles in immune responses [11], this review compiles recent information regarding the relationship
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Fig. 1 Cytokines driving T helper cell differentiation. The diagram illustrates the cytokines required for differentiation from naı¨ve T cells (Th0) to Th1, Th2 or TH17 helper cells. IL-1b, IL-6, IL-21 and TGFb are required for Th0 cell differentiation into Th17 helper cells
Fig. 2 The positive feedback between Th17 and innate immune cells. The figure highlights the pathway, showing Th17 in a positive feedback loop that induces macrophages (MU) and dendritic cells (DC) to produce IL-1b, IL-6 and TGF-b via IL-17A
and IL-12 are the main cytokines that induce the Th1 subtype, while, IL-4 leads to Th2 differentiation [43]. It has also been documented that IL-6 in parallel with TGF-b and IL-1b induce Th17 differentiation, and IL-23 is important for cell maintenance (Fig. 1) [43]. IL-21 also leads to Th17 lineage development in an autocrine manner [32]. Several cytokines have been implicated in Th17 development, and these increase expression of two transcription factors, RORct and RORa, which induce Th17 differentiation [17]. The transcription factors are also responsible for expression of Th17-related genes, including IL-21, IL-22, IL-26, IL17A and F [17]. Interestingly, Th17 has a positive feedback on innate immunity because IL-6 and IL-1b, which are also inducers of Th17 differentiation and its downstream IL17A production, give rise to the development of innate immune cells, including macrophages and dendritic cells, which in turn produce IL-6 and IL-1b (Fig. 2) [12].
Introducing IL-17A IL-17A is a homodimeric 35-kDa protein containing 123 amino acids [16]. IL-17A induces its signal to target cells via IL-17R (a type I cell-surface receptor), which has three variants, including IL17RA, IL17RB, and IL17RC [27]. IL-17A plays dual roles in immune responses against infection. The first role provides a benefit to the host combating infection [20]; however, it is also implicated in detrimental effects such as autoimmunity and immunerelated disorders [21]. Although IL-17A participates in immune responses against fungal and bacterial infections, there is a limited amount of data regarding the role of this cytokine in immune responses against HBV. The association of IL-17A with immune-related diseases, including inflammatory conditions, has led to the hypothesis that this cytokine may contribute to the pathogenesis of HBV infection, including cirrhosis and HCC.
IL-17A and HBV infection between IL-17A and its main source, Th17 cells, to HBV infection. The review also addresses the current data regarding the roles of IL-17A in the pathogenesis of liver cirrhosis and HCC.
Differentiation of Th17 cells In vivo and in vitro studies have demonstrated that all T helper lymphocytes are derived from naı¨ve T lymphocytes and that the developmental history, exposure to cytokines, and microenvironment of the cell determine what kind of T helper cell will be produced from the precursor [42]. IFN-c
123
As mentioned in the introduction, HBV and immune system responses against infected hepatocytes are responsible for the major clinical presentations of hepatitis, including HCC and liver cirrhosis [5], but a complete and specific immune response against HBV can lead to the eradication of the virus [6] and reduce the risk of subsequent disease. Accordingly, some studies have evaluated the roles and status of IL-17A during various forms of hepatitis B. Gehring et al., demonstrated that, during acute infection, HBV-specific T cells were unable to produce IL-17A in response to infected hepatocytes, suggesting that the inflammation within the liver during these phases of HBV
IL-17A in hepatitis B
infection is not directly related to IL-17A and may be due to the expression of other cytokines [9]. Considering that a major and powerful immune response is induced during acute hepatitis B infections, it may be concluded that IL17A is not important in the development of appropriate immune responses against HBV. However, in contrast to responses to acute HBV infection, several studies have demonstrated that IL-17A is upregulated during chronic hepatitis B infections, especially in patients with liver cirrhosis and HCC. Therefore, it appears that this cytokine could be considered a risk factor for liver complications. For instance, Zhang et al. revealed that, in parallel with IL6R?/CD4? T cell elevation, Th17 responses are also increased in chronically HBV-infected patients [38]. Furthermore, it has been established that IL-6 is increased in parallel to liver injury; hence, it could be concluded that Th17 is one of the main cell types implicated or associated with the pathogenesis of chronic HBV infection. Wang et al. showed that there is an increase in T regulatory lymphocytes in chronically HBV-infected patients [31] and that elevated T regulatory cells is associated with immune suppression and long-term HBV infection. Interestingly, these authors showed that the IL-23/IL-17 pathway-related proinflammatory cytokines were also significantly increased in the patients [31]. Therefore, it seems that T regulatory cells are unable to control Th17 function and that liver pathology can be affected by this pathway. Zhang et al. also demonstrated that, in patients undergoing entecavir treatment, the numbers of HBV-DNA particles and T regulatory cells were decreased, and this was accompanied by a rapid increase in the number of Th17 cells [39]. Interestingly, they also revealed that, although the numbers of Th17 cells were increased, their ability to produce IL17A was decreased [39]. Therefore, it seems that therapy with antiviral drugs can inhibit Th17 function and may result in reduced liver injury. Ye et al. reported that the number of Th17 cells found in livers of chronically HBVinfected patients with severe hepatocellular damage was significantly increased when compared to Th1 cells [36], and these results were also confirmed by Zhang et al., who reported that the number of Th17 cells increased with the severity of liver damage in chronic hepatitis B patients [40]. Furthermore, Chinese researchers reported that increased numbers of Th17 cells are positively associated with elevated serum levels of ALT during severe chronic HBV infection [33]. The negative and positive correlation between Th17 and Th1 cells and ALT, respectively, in chronically HBV-infected patents were reported by Ge and colleagues [8]. Additionally, Xu et al., also found that serum levels of IL-17A are significantly increased in HBVrelated liver diseases, especially in hepatitis-B-related liver cirrhosis [35]. Wang et al. showed that the expression of IL-17A in chronically HBV-infected patients, especially in
liver fibrosis, was significantly increased in comparison to healthy controls [30]. Interestingly, they reported that the levels of IL-17A are strongly correlated with the degree of fibrosis [30]. Sun and colleagues demonstrated that increased levels of Th17 cells are significantly associated with disease progression in patients with HBV-associated liver cirrhosis [28]. Another study on the Chinese population revealed that the Th17:T regulatory cell ratio is an important marker for the diagnosis of liver injury and that an increased ratio is related to the deterioration of liver fibrosis [22]. These results were confirmed by Li et al., and their study showed that an increased Th17:T regulatory cell ratio is indicative of more-severe liver injury and fibrosis [19]. Zhai et al. also reported that the Th17:Treg cell ratio was associated negatively with the survival of HBV-associated acute-on-chronic liver failure patients [37]. Recently, Qi et al. reported that patients with liver failure carried more peripheral Th17 cells in comparison to chronically HBV-infected patients and controls [23]. In addition to studies on acute and chronic infection, previous studies demonstrated that occult HBV-infected patients are also at risk of liver cirrhosis and HCC development [7]. Our previous studies revealed that serum levels of IL-17A are significantly increased in occult HBV-infected patients [1]. Overall, the data presented suggest that Th17 cells and/ or the expression of IL-17A play an important role in the pathogenesis of liver injury in all of the clinical forms of HBV infection. It seems that IL-17A may be involved in several mechanisms that promote HCC in HBV-infected patients. For example, Gu et al. proposed that IL-17A promotes HCC development through AKT, which activates the IL6/JAK2/STAT3 pathway [10] (see Fig. 3). In addition, it has been established that IL-17A expression was significantly and positively associated with STAT3 phosphorylation and elevated tumor vascularity [10]. Furthermore, IL-17A induces its signal to target cells via the STAT3 pathway [32], and accordingly, it was shown that STAT3 knockout mice had no susceptibility to viral infections. Interestingly, type I IFNs, which are among the first immune responses against viral infections, suppress Th17 differentiation and IL-17A expression under in vitro and in vivo conditions [29]. Zhao et al. suggested that IL-17A suppresses T cytotoxic lymphocyte functions by inducing B7-H1(?) macrophages (Mphis) [41]. T cytotoxic lymphocytes are the main adaptive immune responses against tumors. Therefore the decrease in these cells and the complimentary increase in B7-H1(?) macrophages swings the course of the disease towards tumorigenesis. The progression of tumourigenesis is enhanced by IL-17A activation of the NF-kB signaling pathway and subsequent increased expression of MMP2 and MMP9, which are
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M. K. Arababadi et al. Fig. 3 IL-17 promotes HCC development through the AKT pathway and the subsequent increased expression of IL-6, MMP9 and MMP2. IL-6 induces immune cells to express MMP2, VEGF and IL-8. MMP molecules enhance metastasis, while VEGF leads to increased angiogenesis. IL-17 also activates STAT3, MAPK/ ESRK, CJNK and C-FOS signaling pathways via activation of TPL2, which leads to elevation of AP-1 transcription and phosphorylation. Additionally, IL-17 suppresses T cytotoxic lymphocyte functions by inducing B7-H1(?) macrophages
two important factors in the induction of HCC metastasis [18]. Supportive evidence for this model was revealed when Th17 cells were detected in HCCs with metastasis and it was shown that their frequency was also significantly associated with poor prognosis of HCC [18]. IL17A is also able to promote neoplastic transformation in JB6 Cl41 cells through activation of tumor progression locus 2 (TPL2) (Fig. 3) [15].
Conclusion Collectively, it appears that the roles of IL-17A in the induction of appropriate immune responses against viral infections are controversial, and more studies are needed to improve our knowledge. However, the published data regarding Th17 and hepatitis B infection, suggest that IL-17A may play an important role in the development of HBV-related liver diseases, especially the pathophysiology of hepatitis-B-related liver fibrosis, cirrhosis and HCC, and future therapies could be directed towards the control of Th17 functions as an
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intervention to prevent liver injury. Additionally, it has been established that the immune system is suppressed during chronic HBV infection and that the number of T regulatory lymphocytes is increased in these patients, while the number of Th17 cells is increased during liver failure in these patients. Therefore, it is likely that Th17 cell functions are not directly under the control of T regulatory cells and that additional mechanisms are involved in the regulation of Th17 function. There is an urgent need for future studies in this field to improve our knowledge regarding the mechanisms involved in the regulation of Th17 function. Research directed at understanding these control mechanisms may shed light on strategies that can be implemented for the treatment of long-term HBV infections and the control of HBVrelated liver damage. Acknowledgements This project was supported by a grant from the Rafsanjan University of Medical Sciences. None of the authors have any financial, professional or personal conflicts that are relevant to the manuscript. Conflict of interest exist.
The authors declare that no competing interests
IL-17A in hepatitis B
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