Exploring the Impact of Different Inflammatory Cytokines on Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) infection is a global health concern affecting millions worldwide. Chronic HCV infection often leads to liver inflammation and can progress to cirrhosis and hepatocellular carcinoma. Inflammatory cytokines are crucial in modulating the immune response during HCV infection. This review aims to investigate the impact of different inflammatory cytokines on HCV infection and associated immune responses.

This review was conducted to identify relevant studies on the interplay between inflammatory cytokines and HCV infection. The analysis focused on the effects of key inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-gamma (IFN-γ), on HCV replication, immune cell activation, and liver inflammation. The findings reveal that these inflammatory cytokines can significantly influence HCV infection and the subsequent immune response. TNF-α, IL-6, and IL-1 have been shown to enhance HCV replication, while IFN-γ exerts antiviral effects by inhibiting viral replication and promoting immune cell-mediated clearance of infected hepatocytes. Moreover, these cytokines contribute to the recruitment and activation of immune cells, such as natural killer cells, T cells, and macrophages, which play critical roles in controlling HCV infection. Understanding the precise mechanisms by which inflammatory cytokines impact HCV infection is crucial for developing more targeted therapeutic strategies. Modulating the levels or activity of specific cytokines may provide opportunities to attenuate HCV replication, reduce liver inflammation, and improve treatment outcomes. In conclusion, this review highlights the significance of inflammatory cytokines in influencing HCV infection and associated immune responses.

HCV Infection

Hepatitis C virus (HCV) infection is a major health problem that affects millions of people globally (Hassanin et al., 2021). After exposure to HCV, acute hepatitis C infection appears during the first 6 months with 20% to 50% of the infected patients having the chance to spontaneously clear the virus (Li and Lo, 2015). However, once the infection persists for 6 months, chronic infection develops in more than 75% of HCV-infected patients (Ashfaq et al., 2011). Then, ∼20% of chronic HCV patients progress to severe liver diseases. HCV infection can be silent for a prolonged period or progress slowly without symptoms (Baskic et al., 2019). The HCV life cycle entails a series of complex steps that enable the virus to infect hepatocytes, replicate within liver cells, and evade host immune surveillance mechanisms.

Upon encountering hepatocytes, HCV initiates its life cycle by attaching to specific receptors on the hepatocyte surface, facilitating viral entry into the host cell. Key receptors involved in this process include CD81 and SR-B1, which mediate viral attachment and internalization. Following entry, the viral RNA is released into the cytoplasm, where it undergoes translation and polyprotein processing to generate structural and nonstructural viral proteins. These proteins play essential roles in viral replication, assembly, and maturation within the hepatocyte. As the HCV life cycle progresses, the host immune system mounts a multifaceted response aimed at controlling and eliminating the viral infection. It was proved that the HCV components disrupt the interactions among different immune cells during the early infection and affect their functions.

The HCV viral proteins such as core, E1, E2, NS3, NS4A, and NS5A induce defective immune cell phenotype and stimulate the dysregulation of many cytokines secretion which lead to chronic infection (Saha and Szabo, 2014). Several studies documented that a strong host immune response is very essential to control virus replication and overcome the infection (Koziel, 2005; Park et al., 2019). Neutralizing antibodies against HCV and strong adaptive cellular immune responses have been associated with the clearance of HCV infection (El-Awady et al., 2009; El-Awady et al., 2006b). Moreover, the expression of interferon-stimulated genes (ISGs), inflammatory cytokines, chemokines, and interleukins play a crucial role in eradicating the virus and controlling the HCV pathogenesis (Bader El Din et al., 2015; Osburn et al., 2013).

HCV-Induced Inflammation

Inflammation usually happens at the early hepatitis as the virus attacks and injures the liver cells. During HCV infection, the host immune responses and cell-mediated mechanisms of liver cells trigger the release of various inflammatory cytokines. Moreover, the HCV proteins induce severe inflammatory and profibrogenic events in hepatic stellate cells (HSCs) (Bataller and Brenner, 2005; El-Awady et al., 2006b). The activated HSCs have enhanced survival in a nuclear factor kappa B (NF-κB) dependent manner by the Kupffer cells (KCs) and macrophages recruitment. The enrichment of proinflammatory cytokines in the liver converted the activated HSCs into myofibroblast like cells. These cells are highly proliferative and express many inflammatory and fibrogenic cytokines that are responsible for extracellular matrix (ECM) accumulation in the microenviroment (El Abd et al., 2011b; Hernandez-Gea and Friedman, 2011).

In addition, the oxidative stress produced by the reactive oxygen species (ROS) in hepatocytes and HSCs induce DNA damage, enhance proinflammatory cytokines expression, and ECM secretion which leads to liver injury (Osburn et al., 2013). HCV also induces the endoplasmic reticulum stress that increases the intracellular ROS levels and induced inflammatory gene expression by activation of NF-κB, and STAT3. It was documented that the high proinflammatory cytokines secretion levels are responsible for development of systemic and local liver inflammation. The impact of HCV on the host liver and immune system is illustrated in Figure 1. Although the liver cells have compensatory proliferation capacity to regenerate and replace the loss of liver cells, the continuous liver cell destruction and inflammatory cell persistence lead to severe inflammation, scarring of the liver, cirrhosis, and end with hepatocellular carcinoma (HCC) (Bataller and Brenner, 2005).

FIG. 1.

The impact of HCV on the host liver and immune system. After HCV infection, the virus proteins activate the HSC and its transformation to myofibroblast, moreover, HCV infection induce host innate and adaptive response as well as endoplasmic reticulum which will lead to induction of inflammatory cytokines, then accumulation of ECM in hepatic cells causing liver fibrosis. HSC, hepatic stellate cell; HCV, hepatitis C virus; ECM, extracellular matrix.

Inflammatory Cytokines in HCV Infection

The inflammatory or proinflammatory cytokines are large group of signaling proteins that are secreted from immune cells such as macrophages, T helper cells, and other cells that induce inflammation (Gaffen and Liu, 2004). They play key roles in hematopoiesis, immunity, and inflammation. The HCV particles and proteins (core, NS3, NS4A, and NS5A) and double-stranded HCV RNA (dsRNA) trigger the production of several inflammatory cytokines and chemokines. During HCV infection, the interaction between chemokine-chemokine receptor in the liver play important role in the recruitment of T cells to the inflammation sites. Several proinflammatory cytokines and chemokines are expressed such as interleukin1 (IL-1), IL-6, IL-8, IL-12, IL-17, IL-18, macrophage inflammatory protein 1α (MIP-1α), IP-10, tumor necrosis factor α (TNF-α), and interferon gamma (IFNγ). The functions of these inflammatory cytokines are summarized in Table 1.

Table 1.

Functions of Inflammatory Cytokines

Cytokine	Type of cells	Functions
IL-1	Macrophages HSCs	Initiates the innate immunity responses. Promotes inflammation and recruits immune cells to the site of infection. Induces the acute phase and contributes to liver damage during chronic HCV infection.
IL-2	Th1 cells	Activates the proliferation of T cells, including CD4⁺ and CD8⁺ T cells. Enhances the cytolytic activity of NK cells and the development of regulatory T cells Controls the immune response and is essential for controlling HCV infection.
IL-6	Macrophages dendritic cells T and B cells	Has stimulatory and inhibitory effects on HCV progression and liver fibrogenesis. Important proregenerative and protects against hepatocytes injury, damage, and reducing liver inflammation Associated with immune reaction and the acute phase response. Plays a role in promoting inflammation and lead to the development of liver fibrosis during chronic HCV infection.
IL-8	Blood cells different tissues	Recruits neutrophils and T cells to the site of infection. Leads to inhibition of IFN antiviral actions and HCV persistence, pathogenesis, and lack of response to IFN therapy Contributes to the severe inflammatory response during HCV infection.
IL-17	CD4⁺ Th17 T cells	Involved in the recruitment of neutrophils and the production of proinflammatory cytokines. Stimulates KCs and HSCs to produce many cytokines. Promotes various neutrophil attracting chemokines and proinflammatory mediators, leading to tissue injury. Contributes to Liver inflammation and fibrogenesis.
IL-18	Activated Macrophages Dendritic Cells Kupffer Cells	Enhances the production of IFN-γ, promotes Th1 responses, and combines with IL-12 to induce cell-mediated immunity Induces macrophages to produce TNF-α and NO which leads to cell death. Exhibit antiviral and antitumor effects by stimulating the FasL expression, which provides defense against HCV Can also cause liver inflammation, necrosis, and fibrosis in HCV patients.
IL-22	Liver-resident innate lymphoid cells Th17 & Th22 cells	Important for tissue repair, regeneration and wound healing. Can be either protective or pathogenic cytokine according to the tissues. Upregulates the expression of chemokines and matrix metalloproteinases, which promote inflammation and HCC. Protects against liver injury during HCV infection by promoting hepatocyte survival and regeneration.
IL-33	Dendritic cells macrophages damaged epithelial cells	Involved in promoting Th2 immune responses, many cytokines, and tissue repair. Activates NF-κB and MAP kinase signal pathways and triggers tissue injury and inflammatory responses. Contributes to the modulation of liver inflammation.
TNF-α	Activated macrophages, CD4⁺ lymphocytes natural killer cells	Potent proinflammatory cytokine that contributes to liver inflammation and fibrosis during chronic HCV infection. Activate HSC, immune cells, and prevent hepatocyte apoptosis which leads to liver fibrosis
TGF-β	Most immune cells Epithelial cells Dendritic cells Fibroblasts	Multifunctional cytokine involved in tissue repair and fibrosis. Promotes liver fibrosis in response to HCV infection. Key mediator of HSC activation and differentiation into fibrogenic myofibroblasts and leads to liver fibrosis. Has immunosuppressive properties and can modulate immune responses during HCV infection
IFNs	Virus-infected cells Macrophages NK cells T cells	Type I (IFN-α & IFN-β) and type III (IFN-λ) are crucial for the innate immune response against HCV. Inhibit viral replication and stimulate antiviral mechanisms in infected cells. Type II (IFN-γ) plays a role in promoting antiviral immunity and modulating adaptive immune responses against HCV.

HCV, hepatitis C virus; ECM, extracellular matrix; HSC, hepatic stellate cell.

These cytokines mediate the innate immune response against HVC infection and promote the inflammatory reactions (Kumar et al., 2016). Accordingly, these inflammatory cytokines and their receptors are considered the key regulators of liver inflammation and their increased expression levels have been associated with irreversible liver injury, hepatic fibrogenesis, and development of HCC in HCV-infected patients (Nishitsuji et al., 2013). Moreover, several studies showed an association between cytokines and ISG polymorphisms and the progression of HCV disease (Bader El Din et al., 2015; Morozov and Lagaye, 2018). The different inflammatory cytokines profile secreted in HCV infection is shown in Figure 2.

FIG. 2.

The different inflammatory cytokines profile secreted in HCV infection. Inflammatory cytokines released by virus-infected cells, such as IFNs, IL-1, IL-2, IL-6, IL-8, TNF-α, IL-17, IL-18, IL-22, and IL-33, and TGF-b, inducing a potent inflammatory response, attracting, and activating macrophages, dendritic cells, mast cells, and NK cells, to the site of infection. Furthermore, these cytokines are involved in the induction of adaptive immunity (Th1/Th 2/Threg/TCL and B cells), while cytokines such as IL-4, IL-10, IL-13, and TGF-β inhibit the inflammatory cytokines. TGF, transforming growth factor.

Interleukin-1

IL-1 is a potent proinflammatory cytokine with several biological effects. It is produced mainly by human macrophages and play role in initiating the innate immunity responses. The IL-1 gene family on chromosome 2q13–21 and encodes for 3 proteins the agonists IL-1α, -1β, and receptor antagonist (IL-1RN) (Walker et al., 2018). Binding of IL-1 to the cell surface IL-1 type I receptor activates many downstream signaling pathways such as extracellular signal-regulated kinase (ERK), IκB kinase/Nuclear factor kappa B (IKK–NF-κB), p38, and Jun N-terminal protein kinase (JNK). IL-1α is secreted by HSCs and has an important role to induce the acute phase response of liver inflammation and to activate the KCs (Winwood and Arthur, 1993).

IL-1α is a damage-associated molecular pattern (DAMP) and mediates the stimulation of HCV-infected hepatocytes, and the expression of inflammatory cytokines such as Macrophage Inflammatory Protein-1 (MIP-1α and MIP-1β), IL-6, and IL-8 leads to HCV-related inflammation (Nishitsuji et al., 2013). Also, IL-1 regulates the immune response, enhances ISGs expression, and induces antiviral activity to eliminate the virus (Ichikawa et al., 2002; Tawfik et al., 2018).

IL-1α signaling via the IL-1R influences the IL-1β transcription and secretion from monocytes. It was reported that IL-1α induces neutrophils infiltration while IL-1β induces macrophages recruitment and activates inflammatory reactions (Di Paolo and Shayakhmetov, 2016; Rider et al., 2011). IL-1α affects several IFN-γ activities (Hurgin et al., 2007) and augmented hepatic expression of IL-1α, IL-2, and TNF-α was demonstrated in chronic HCV patients (Kasprzak et al., 2004). Recently, it was shown that higher Serum IL-1α level in chronic HCV patients is associated with the severity of liver diseases (Tawfik et al., 2018).

Also, HCV induced the production of IL-1β by different stimulation such as Toll-like receptor (TLR) ligands, or muramyl dipeptide-mediated NOD-like receptor (NLR) and Nod-like receptor P3 (NLRP3) cell death independent pathway. In HCV-infected liver cells, the hepatic macrophages or KCs produce IL-1β. The high IL-1β concentration within HCV-infected liver cells stimulates synthesis of many proinflammatory cytokines, chemokines, and expression of several immuneregulatory genes that promote liver injury, inflammation, and fibrosis (Dinarello, 2018).

IL-1 β extends the HSC survival, downregulates bone morphogenic protein and activin membrane-bound inhibitor (BAMBI) and upregulates fibrogenic tissue inhibitor of metalloproteinase 1 (TIMP-1) (Dinarello, 2018; Rider et al., 2011). Moreover, different genetic polymorphisms in IL-1β gene and its receptor, which affects the production and secretion of IL-1β, are linked to HCV liver disease severity. The genotype CT at polymorphism IL-1β (-511) showed increased risk of cirrhosis (Kasprzak et al., 2006).

Interleukin-2

IL-2 is a proinflammatory cytokine which is secreted by Type 1 T helper (Th1) cells and activates the regulatory T cells to produce the IFN-γ and TNF-α. IL-2 is essential for growth and survival of T-lymphocytes, some nonlymphoid cells, and natural killer (NK) cells. Also, it enhances the cytolytic activity of NK cells and development of regulatory T cells, which control the activated T cell expansion and apoptosis (Gaffen and Liu, 2004; Sakaguchi et al., 2008; Smith and Humphries, 2009). Moreover, IL-2 controls the immune response by affecting the survival and differentiation of both the immune memory cells and regulatory T cells as well as contributes to the propagation of antigen-specific immune responses (Capobianco et al., 2016; Malek et al., 2008).

During HCV infection, specific CD4⁺-T cells secrete Th1 cytokines (IL-2, TNF-α, IFN-γ), which play critical key role in regulating adaptive immune response. These cytokines enhance the recruitment of neutrophil and macrophage, which promote the cell-mediated immune reaction and lead to inflammatory response. The augmented intrahepatic expression of these cytokines was reported in chronic HCV patients and the expression levels were highly correlated with the pathogenesis of liver disease. Also, it was documented that elevated circulating of IL-2 levels in HCV patients were associated with the liver inflammation grade and fibrosis stage. Nevertheless, higher IL-2 mRNA expression level was detected in HCV patients who did not response to interferon α (IFN-α) treatment (Bozkaya et al., 2000).

Generally, patients with chronic hepatitis had been shown statistically significant difference in the level of IL-2 and TNF-α compared to controls (Mourtzikou et al., 2014). Recently, it was reported that the treatment with anti-inflammatory compounds reduce the IL-2 expression level in Peripheral blood cells infected with HCV in vitro (El-Deeb et al., 2018).

Interleukin-6

IL-6 is a proinflammatory cytokine that has a critical role in of acute phase responses, immune reactions, chronic inflammation, and hematopoiesis. IL-6 is produced promptly by different cell types such as macrophages, dendritic cells, and T and B cells in response to any tissue injuries or infectious molecules (Tanaka et al., 2014). The pathogen-associated molecular patterns usually bind to pattern recognition receptors such as RIG-1-like receptors or TLR and induce the inflammatory cytokines production. IL-6 is an important proregenerative and acute phase inducer factor in the liver. It is identical with hepatocyte stimulating factor 2, which induces the liver to synthesize acute phase proteins such as C-reactive protein, fibrinogen, haptoglobin, and serum amyloid A (SAA) (Heinrich et al., 1990). It has been shown that high SAA level leads to amyloid fibril deposition, which results in progressive chronic inflammatory reactions and deterioration in many organs (Gillmore et al., 2001).

Intrahepatic expression of Th1-associated cytokines IL-6, IL-10, and TNF-α have been associated with the immune response to HCV infection and related to progressive liver injury. IL-6 with IL-23 and transforming growth factor (TGF)-β lead to the differentiation of Th17 cells, which secrete cytokines cause many inflammatory reactions such as IL-1, TNF α, IL- 17A, and IL-17F. The HCV NS5A and core proteins stimulates the innate immune response and upregulates TLR4 and TLR2 expression in B cells to produce IL-6, which causes increased inflammatory response (Feldmann et al., 2006). In cell culture experiments, the IL-6 derived from KC promotes HSC proliferation and survival. It was proved that increased IL-6 secretion plays a critical role in the pathogenesis of hepatitis C disease and liver fibrosis (Falzarano et al., 2013).

However, different studies showed conflicting results regarding the role of IL-6 in liver fibrosis. IL-6 can negatively or positively regulate liver fibrosis by targeting different types of liver cells.

IL-6 protects against hepatocytes injury and damage, thus reducing liver inflammation which causes fibrosis, while it may promote HSC survival and proliferation and enhance liver fibrosis. Therefore, the balance between the stimulatory and inhibitory effects of IL-6 determines the role of IL-6 on liver fibrogenesis and HCC progression (Baskic et al., 2019). High IL-6 levels are related to viral persistence and resistance to treatment. Moreover, it was proved that different genetic polymorphisms in IL-6 influence the outcome of HBV and HCV liver disease as well as development of cancer (Cabibbo et al., 2017). Recently, El-Deeb et al., 2018, indicated that IL-6 polymorphisms (-174 G/C, -597G/A, and -572 G/C) affect the expression level and are associated with the susceptibility to chronic HCV infection.

Interleukin-8

IL-8 is a chemoattractant and proinflammatory cytokine produced by blood cells and different tissues and its synthesis is stimulated by IL-1 and TNF-α. IL-8 releases in response to any inflammatory or cellular stress stimuli and bacterial and viral infection. It has a critical role in wound healing and inflammation and attracts and activates neutrophils in inflammatory regions, which leads to influx of neutrophils and severe inflammation (Bickel, 1993).

Serum elevated levels of IL-8 and TNF-α were documented in HCV-infected patients. HCV NS5A protein activates the IL-8 promoter and induces its mRNA and protein expression. It was found that the stimulation of IL-8 by HCV NS5A leads to inhibition of interferon antiviral actions in vitro. Therefore, the high IL-8 level is associated with the HCV persistence, pathogenesis, and lack of response to IFN therapy (Polyak et al., 2001). It was proved that during HCV infection, activated HSCs stimulate the hepatocytes to express IL-6, IL-8, MIP-1α, and MIP-1β, which causes liver cell injury and development of chronic hepatitis (Nishitsuji et al., 2013). It was demonstrated that IL-8 serum levels before and after interferon treatment are associated with HCV infection and resistance to therapy (Maysaa El Sayed et al., 2011).

Moreover, IL-8 promotes tumor growth, angiogenesis, and metastasis in several cancers, and serum IL-8 was elevated in HCC patients and associated with poor overall survival rate (Qazi et al., 2011). It was found that the functional IL-8 polymorphism (−251A/T) influences the progression from hepatitis to cirrhosis then HCC (Qin et al., 2012). The IL-8 level has been shown to differentiate between HBV patients, chronic HCV patients, and nonviral disease patients as well as it can differentiate between patients with or without HCC (Estevez et al., 2017). Recently, a human monoclonal antibody (HuMax-IL8) which blocks IL-8 is used in Phase I trial to treat solid tumors (Bilusic et al., 2019).

Interleukin-17

IL-17 is mainly produced from CD4⁺ Th17 T cells, and it is upregulated in HCV infection. Specific HCV-Th17 cells affect the immune responses and correlated with intrahepatic inflammation and fibrosis severity. In HCV patients, it was reported the expansion of HCV-specific Th17 cells in hepatic tissue and it was correlated with the severe liver damage (Chang et al., 2018). However, Th17 cells have potential beneficial aspects in host anti-HCV defense and it has been shown that boost of Th17 cells are associated with the control of HCV infection and spontaneous clearance.

IL-17A is a strong inflammatory cytokine with several activities. Also, IL-17 is a potent chemoattractant for neutrophils (Abdel Haleem et al., 2013). It stimulates KCs and HSCs to produce TNF-α, IL-6, IL-23, and TGF-β through activation of NF-κB and STAT3. Both L-17A and IL-17F stimulate other proinflammatory mediators and several neutrophil attracting chemokines, which promote tissue injury and inflammation (Dong et al., 2008). IL-17 stimulates the HSCs transformation to myofibroblasts, the ECM synthesis, and cell contractility, which causes changes in microstructure and microcirculation of the liver (Hernandez-Gea and Friedman, 2011). It was shown previously that IL-17A- and IL-17 RA-deficient mice exhibit decreased liver fibrosis (Li et al., 2016).

Therefore, the Th17 cells/IL-17 axis has a critical role in fibrogenesis, progressive liver disease, and treatment response in HCV patients. The expression of IL-17F is elevated in HCV patients with fibrosis and HCC (Ibrahim et al., 2022; Wu and Santella, 2012). Finally, polymorphisms in IL17 gene are risk factor for liver fibrosis and HCC development (Li et al., 2016).

Interleukin-18

IL-18 is a proinflammatory cytokine known as IFN-γ inducing factor and is produced by different cell types such as activated macrophages, dendritic cells, and KCs. It belongs to IL-1 superfamily and can control the innate and adaptive immune response. IL-18 plays an important role in the activating T cell and triggering a cytokine cascade and Th1 responses. Also, IL-18 induces macrophages to produce TNF-α and nitric oxide (NO), which leads to cell death. IL-18 can exhibit antiviral and antitumor effects by stimulating the expression of Fas-ligand (FasL) in the liver and activated NK cells (Sharma et al., 2009).

During infection, IL-18 binds to IL-18 receptor and combines with IL-12 to induce cell-mediated immunity, which then causes severe inflammatory reactions (Dinarello, 2018). Antibodies against IL-18 have been used in a murine model to prevent liver damage. In HCV patients, a significant correlation was found between high IL-18 plasma levels and liver inflammation, necrosis, and Child–Pugh liver severity in cirrhotic patients (Asakawa et al., 2006). The extracellular IL-18-binding protein binds with a high affinity to IL-18 and suppresses its activity. The treatment of HCV patients with IFN therapy α increases the IL-18-binding protein by 3 to 24-fold and this is crucial for the regulation of liver inflammation and fibrosis. Moreover, it was revealed that high IL-18 receptors level was a predictor of poor outcome in HCV patients who developed HCC. Polymorphisms in IL-18 promoter are associated with liver diseases and HCC development in HCV patients (Asakawa et al., 2006).

Interleukin-22

IL-22 is expressed by liver-resident innate lymphoid cells (ILC2) or Th17 and Th22 cells and has been involved in cell proliferation, tissue repair, and wound healing. Administration of IL-22 in vitro leads to increased expression of IL-20 by activating STAT3. According to the tissues and disease, it is stated that IL-22 may be either protective or pathogenic cytokine. It was reported that the administration of IL-22 is sufficient to stimulate inflammation and the produced systemic inflammatory effects dependent on the amount of IL-22 (Liang et al., 2010). Also, in the liver, IL-22 can upregulate the expression of matrix metalloproteinases and chemokines, induce neutrophil migration and promote HCC development. Conversely, IL-22 promotes liver progenitor cells, hepatocyte proliferation, inhibit apoptosis, and downregulate fibrosis (Cobleigh and Robek, 2013). In mice liver, IL-22 suppresses fibrosis by inducing HSC senescence and promoting hepatocellular proliferation (Asrani et al., 2018).

Recent studies in HCV patients demonstrated that both IL-20 and IL-22 cytokines expressed by immune cells and hepatocytes are related to liver fibrosis. IL-20 is a profibrogenic cytokine, which induces the HSCs activation, proliferation, migration, and TGF-β1 upregulation. Recently, it was proved that the inhibition of IL- 20 and IL-20R decreased liver injury and fibrosis (Lee et al., 2017). Also, IL-22 influences on the pathogenesis and treatment outcome of HCV infection. In hepatitis C patients, high IL-22 level activates HSCs, causes liver injury, fibrosis progression, and can predict the prognosis of liver cirrhosis (Liu et al., 2017). Hennig et al., 2007 showed that genetic variation in IL-22 genes plays a modulatory role in HCV infection and determine the outcome of the disease (Hennig et al., 2007). Furthermore, the polymorphism in the IL-22 gene influences treatment response and viral clearance (Coppola et al., 2015).

Interleukin-33

IL-33 is a newly described IL-1 family member and it is a multifunctional cytokine implicated in various diseases. It is secreted by dendritic cells, macrophages, and damaged epithelial cells. It binds to heterodimer receptor composed of ST2- and IL-1R-associated protein (IL-1R3). IL-33 induces Th2 response and many cytokines production. Also, it activates NF-κB and MAP kinase signal pathways. IL-33 is considered as DAMP that triggers tissue injury and inflammatory responses (Wang et al., 2018). It was reported that high soluble ST2 serum level is a biomarker of liver injury, while high IL-33 serum level is associated with the progression of liver damage and fibrosis (Askoura et al., 2022). It was proved that mice deficient in IL-33 or depleted from ILC2 have reduced liver fibrosis (McHedlidze et al., 2013).

IL-33 is considered as key mediator of liver fibrosis and plays an important role in the profibrotic cascade in vivo. IL-33 is released in response to chronic liver cells and leads to activation of ILC2 resident in the liver. Activated hepatic ILC2 produce IL-13, which in turn promotes activation and differentiation of HSC through IL-4Rα- and STAT6. Therefore, sustained release of IL-33 in the liver leads to ECM activation, pathologic tissue remodeling, and fibrosis (Tan et al., 2018).

Tumor necrosis factor-α

TNF-α is a highly proinflammatory cytokine which is involved in many inflammatory events. TNF-α has many diverse effects such as HSC activation, immune cell activation, and hepatocyte apoptosis (Bader El Din et al., 2016). TNF-α is produced from HCV-activated immune cells such as macrophages, CD4⁺ lymphocytes, and Natural Killer cells. TNF-α plays an important role in liver fibrosis by preventing HSC apoptosis, downregulate BAMBI, and upregulate TIMP-1 (Talaat et al., 2012). It was documented that mice deficient in TNF-α and TNF receptor type I has reduced cholestatic liver fibrosis (Trujillo-Murillo et al., 2010). Hepatic TNF-α has been correlated with increased liver injury, inflammation, and hepatic fibrosis. HCV patients with severe liver fibrosis showed higher levels of both TNF and IFN-γ cytokines (de Souza-Cruz et al., 2016).

Recently, it was shown that both TNF-α -238 and -308 polymorphisms affect liver inflammation degree and fibrosis stage (Bader El Din et al., 2017; Mourtzikou et al., 2014).

Transforming growth factor-β

TGF-β is a cytokine that plays a complex role in HCV infection and it is secreted from immune cells, dendritic cells, epithelial cells, and fibroblasts. TGF-β is a potent inducer of liver fibrosis, including the deposition of ECM proteins such as collagen (Salum et al., 2018). In chronic HCV infection, persistent inflammation leads to the activation of HSCs, which are the major cell type responsible for producing collagen and promoting liver fibrosis. TGF-β is a key mediator of HSC activation and differentiation into fibrogenic myofibroblasts, contributing to the development of liver fibrosis. (Bader El Din et al., 2017). Also, TGF-β has immunosuppressive properties and can modulate immune responses during HCV infection. It can inhibit the proliferation and activation of various immune cells, including T cells, NK cells, and dendritic cells. This immunosuppressive effect of TGF-β may contribute to viral persistence and hinder the elimination of HCV (Zou et al., 2021).

TGF-β can induce a process called epithelial-mesenchymal transition (EMT), which is characterized by the transformation of epithelial cells into mesenchymal cells with increased migratory and invasive properties. EMT has been implicated in liver fibrosis and HCC development, both of which can be complications of chronic HCV infection. TGF-β-mediated EMT may promote the progression of liver disease in HCV-infected individuals (Benzoubir et al., 2013; Salum et al., 2018). TGF-β can suppress the antiviral immune response against HCV. It can inhibit the production of interferons and other cytokines involved in the antiviral defense mechanism. In addition, TGF-β can impair the function of NK cells and cytotoxic T lymphocytes (CTLs), which are important for controlling HCV replication and eliminating infected cells (Márquez-Coello et al., 2021).

The role of TGF-β in HCV infection is complex and context-dependent. While it promotes fibrogenesis and immunosuppression, it may also have protective effects by regulating inflammation and tissue repair. The overall impact of TGF-β on HCV infection likely depends on the balance between its profibrotic and immunosuppressive effects (Guo et al., 2019). In HCV-infected patients, Bader El Din et al., (2017) reported that polymorphism in TGF-β1 leads to liver inflammation and higher fibrosis grade.

Interferons

Interferons are a group of signaling proteins that play a vital role in the body's immune response against viral infections, including HCV infection. There are 3 main types of interferons: type I (IFN-α and IFN-β) and type II (IFN-γ). IFN-α and -β and are secreted by virus-infected cells while IFN-λ is secreted by T cells, macrophages, and NK cells.

Interferon-α

Type I interferons include several subtypes, with IFN-α and IFN-β being the best-studied and most commonly used in clinical settings. They are produced by various cells, including immune cells, in response to viral infections. In the context of HCV infection, type I interferons exhibit antiviral activity by inhibiting viral replication, promoting apoptosis in infected cells, and enhancing the immune response against the virus. They also have immunomodulatory effects that can help regulate the immune system's response to HCV (REF). IFN-α plays a significant role in the immune response against HCV infection. It has been widely studied and used as a therapeutic agent for the treatment of chronic HCV infection. IFN-α has direct antiviral effects against HCV (Poynard et al., 2002).

It inhibits viral replication by inducing the expression of antiviral proteins, such as protein kinase R (PKR) and 2',5'-oligoadenylate synthetase (OAS), which interfere with viral protein synthesis and replication. IFN-α also modulates the immune response against HCV. It enhances the activity of NK cells, dendritic cells, and CTLs, which are important in eliminating HCV-infected cells. IFN-α promotes antigen presentation and the production of proinflammatory cytokines, contributing to the immune response against HCV (Lee et al., 2015).

IFN-α has been used in combination with ribavirin, an antiviral drug, for the treatment of chronic HCV infection. This combination therapy has shown improved sustained virological response rates compared to IFN-α monotherapy (Hsu et al., 2015). However, it is important to note that the efficacy of IFN-α-based therapy is limited, and the treatment success rates vary depending on factors such as HCV genotype, patient characteristics, and viral load (Hsu et al., 2013). IFN-α therapy was associated with various adverse effects, which may limit its tolerability and adherence (Lee et al., 2015). Many therapeutic approaches have been studied to treat HCV infections (El Abd et al., 2011a; el-Awady et al., 2006a). Recently, with the advent of direct-acting antiviral (DAA) therapies, which directly target specific steps in the HCV replication cycle, IFN-α-based regimens have largely been replaced (Arif et al., 2003; Zeng et al., 2020).

Interferon-β

IFN-β has also been studied in the context of HCV infection, although its role in HCV treatment is less well-established compared to IFN-α. IFN-β exhibits direct antiviral activity against HCV. It induces the expression of antiviral proteins that interfere with HCV replication, such as PKR and OAS (Kanda et al., 2017). By targeting viral replication, IFN-β helps inhibit HCV replication within infected cells. IFN-β has immunomodulatory effects that can influence the immune response against HCV. It can enhance the activity of immune cells, including NK cells and CTLs, which are involved in the elimination of HCV-infected cells (Shimozono et al., 2015). In addition, IFN-β has been shown to regulate the production of proinflammatory cytokines, which can modulate the immune response during HCV infection. Compared to IFN-α, IFN-β has not been extensively studied or used in clinical practice for HCV treatment (Sasaki et al., 2015).

Most clinical trials and treatment guidelines have focused on IFN-α -based regimens or, more recently, DAA therapies have revolutionized HCV treatment with higher efficacy and improved tolerability (Tanabe et al., 2007).

IFN-γ: - IFN-λ

IFN-γ plays a crucial role in the immune response against HCV infection. IFN-γ is a cytokine produced by immune cells such as T cells and NK cells (Attallah et al., 2016). It has potent antiviral activity against HCV. IFN-γ activates intracellular signaling pathways that result in the production of antiviral proteins, which can inhibit HCV replication within infected cells. IFN-γ stimulates the immune system to mount an effective antiviral response against HCV. It enhances the activation and function of various immune cells, such as macrophages, dendritic cells, and cytotoxic T cells (Wang et al., 2017). These cells are important for the clearance of HCV-infected cells and the generation of adaptive immune responses. Moreover, IFN-γ induces the expression of a wide range of ISGs within infected cells.

These ISGs have diverse antiviral functions, including inhibiting viral replication, modulating immune responses, and promoting apoptosis of infected cells. IFN-γ plays a role in regulating T cell responses during HCV infection (Romero et al., 2006). It promotes the differentiation of CD4⁺ T cells into Th1 cells, which produce IFN-γ and other cytokines involved in the antiviral response. Th1 cells are important for activating other immune cells and controlling viral replication (Mascia et al., 2017).

IFN-γ contributes to the inflammation observed in the liver during chronic HCV infection. While inflammation is a part of the host's immune response, excessive or prolonged inflammation can lead to liver damage (Luo et al., 2013). IFN-γ, along with other proinflammatory cytokines, can contribute to liver injury in HCV-infected individuals. While IFN-γ plays a significant role in the immune response against HCV, the virus has evolved mechanisms to evade and subvert the host immune system, including interfering with IFN signaling pathways. This contributes to the ability of HCV to establish chronic infection in many individuals (Bansal et al., 2011).

Interferon-λ

IFN-λ is considered a very important part of the immune response against HCV infection. It enhances the immune lysis of HCV-infected cells, prevent the liver inflammation and fibrosis by an effect on TGF-beta, and an effect on HCV-induced carcinogenesis (Chigbu et al., 2019). IFN-λ predominantly affects the epithelial cells, which are present in the liver, respiratory tract, and gastrointestinal tract. The IFN-λ is a promising therapeutic target for HCV infection due to its ability to elicit antiviral responses without producing inflammation and adverse effects. IFN-λ activates the JAK-STAT signaling pathway to produce its antiviral actions (El-Awady et al., 2012). IFN-λ phosphorylates STAT proteins, which subsequently go to the nucleus and control the production of many ISGs. These ISGs encode proteins that have a range of antiviral properties, including the ability to prevent viral replication, enhance the clearance of the HCV, and strengthen the host immune system against HCV (Urbanowicz et al., 2019).

Several studies have demonstrated that IFN-λ can successfully prevent HCV replication in both in vitro and animal infection models. Moreover, research conducted on people has indicated a correlation between variations in the genes that encode IFN-λ receptors and the evolution of HCV infection as well as the response to IFN- treatment. Certain polymorphisms highlight the importance of IFN-λ signaling in the host immune response against HCV infection and the HCC development (Read et al., 2017).

Conclusion

This review highlights the significant role of inflammatory cytokines in determining the outcome and progression of HCV infection. The interplay between the HCV infection and the inflammatory cytokines is highly dynamic and complicated. Dysregulation of cytokine signaling and expression can lead to chronic inflammation, liver damage, and increased susceptibility to HCV-related complications. The balance between pro- and anti-inflammatory signals is crucial to control how the HCV infection develops and determines the impact on viral clearance, liver damage, chronicity, and the response to antiviral therapy. Recently, many of HCV therapeutic strategies target the cytokine signaling pathways to modulate the host immune response and enhance the effectiveness of HCV infection treatment.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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