IL-18 and IL-1β Gene Polymorphisms: The Plausible Risk Factors for Chronic Hepatitis B

Abstract

Chronic inflammation is the main risk factor for induction of liver cirrhosis and also hepatocellular carcinoma in chronic hepatitis B (CHB) patients. Although our knowledge is growing regarding molecular mechanisms of immune responses against viruses, the main mechanisms that lead to the progression of chronic inflammation and then CHB are yet to be clarified. IL-18 and IL-1β are the members of the IL-1 family and produced in the cytoplasm of a wide range of immune and nonimmune cells and activated by inflammasome pathways. The cytokines play key roles in the pathologies of CHB. IL-18 and IL-1β productions are altered in CHB patients. It has been hypothesized that the polymorphisms within IL-18 and IL-1β genes may be the main reasons for the induction of chronic inflammation in CHB patients. This review article discusses the related investigations regarding the main correlation between the polymorphisms within IL-18 and IL-1β genes and CHB pathogenesis.

Introduction

Hepatitis B is a prevalent liver-associated disorder, which has various clinical presentations (3). The chronic form of the disease is common and several cases do not show the hepatitis-related clinical presentations (3). However, interactions between the pathogens associated molecular patterns (PAMPs) of the hepatitis B virus (HBV) with innate immunity receptors result in a chronic inflammation in patients who suffer from chronic hepatitis B (CHB) (44). It has been hypothesized that the chronic inflammation is the main cause of hepatitis B-related complications, including hepatocellular carcinoma (HCC) and liver cirrhosis (LC) (24,52). Thus, detection of the responsible molecular mechanisms that lead to induction of CHB may be associated with new treatment strategies to overcome the form of hepatitis B.

Innate immunity consists of several cell membrane and cytoplasmic receptors that recognize PAMPs and then activate intracellular signaling pathways, which led to activation of the host cell and also other innate and adaptive immune cells (44). Inflammasomes are a set of intracellular innate immune receptors, which recognize intracellular PAMPs and damage associated molecular patterns (47). They also are activated by other innate immune receptors such as toll-like receptors (TLRs), which are entitled inflammasome priming (4).

Inflammasomes consist of various molecules such as NOD-like receptor pyrin domain containing (NLRP), NOD like receptor CARD containing (NLRC) and absent in melanoma 2 (AIM2) (15). All of the inflammasomes activate the pathways, which lead to phosphorylation of caspase-1 and then activation of the enzyme. Caspase-1 is the molecule responsible for cleavage of pro-IL-1β and pro-IL-18 to produce mature IL-1β and IL-18, respectively (36). IL-1β and IL-18 are the proinflammatory cytokines and play significant roles either against microbial infections or induction of tissue damages during inflammatory-based diseases (32). The roles played by the cytokines against HBV have also been documented by several studies (2,21,25,27,40,49,58).

Accordingly, activation of innate and adaptive immune cells, increased expression of addressing molecules on the endothelial cells of the damaged/infected tissues, upregulation of proinflammatory cytokines, and increased number and activation of T regulatory lymphocytes are the most important functions of IL-1β and IL-18 during infection with HBV (2,21,25,27,40,49,58). As mentioned previously, chronic low responses of the immune system to the HBV-PAMPs is the reason for the induction of chronic inflammation in CHB patients. Accordingly, low continuous productions of mature IL-1β and IL-18 in CHB patients have also been reported by the investigators (28). The mechanisms that lead to low production of IL-1β and IL-18 in CHB patients have yet to be clarified. Variations in the genes of the cytokines are the plausible mechanisms for low chronic production in human chronic inflammation-related disease (21).

Therefore, it has been hypothesized that IL-1β and IL-18 gene polymorphisms may be considered risk factors for alteration in the production of IL-1β and IL-18 (45) and then the development of CHB. This review article discussed new information regarding the relationship between CHB and the polymorphisms within IL-1β and IL-18 genes.

Introduction of IL-1β and IL-18

IL-18, which is known as interferon-gamma-inducing factor, IL-1g, iboctadekin, and IL1F4, is a proinflammatory cytokine and produced by several lineages such as Eukaryota, Chordata, Metazoa, Mammalia, Primates, Catarrhini, and Homo (30). Its gene is located at 11q23.1 and consists of six exons and five introns, and is conserved in Rhesus monkey, chimpanzee, dog, mouse, cow, and rat. IL-18 gene lacks TATA box, while has two distinct promoters. Promoter 1 and 2 are located at upstream of untranslated exon 1 and 2, respectively (30). Its promoters and exons contain various single-nucleotide polymorphisms (SNPs), including −667G/T, −148G/C, +8925C/G, +13925A/C, 607 A/C, −656 T/G, −137 G/C, −1297 T/C, and 105 A/C (34), hence, they may alter the expression of the cytokine.

IL-18 is a member of the IL-1 family and structurally similar to IL-1β. Pro-IL-18 is produced by various cells, including macrophages, intestinal epithelial cells, keratinocytes, dendritic cells, astrocytes, and osteoblasts. However, its receptor (IL-18R) is expressed on either innate or adaptive immune cells and also nonimmune cells such as smooth muscle cells, epithelial cells, endothelial cells, keratinocytes, fibroblasts, chondrocytes, and melanocytes (1,19,43). Therefore, several cell systems can recognize viral PAMPs and produce mature IL-18, and then activate immune cells.

IL-1β is another member of the IL-1 family, which is activated following cleavage activities of inflammasome-related caspase-1. IL-1β, which is known as IL1F2, is another proinflammatory cytokine. IL-1β gene is located at 2q14.1 and consists of seven exons and six introns. In contrast to IL-18 gene, IL-1β gene has TATA box, which contains the core promoter region and two important binding sites for the leucine zipper containing transcription factor (TF), CCAAT/enhancer binding protein-β, and the myeloid-specific Ets domain containing TF PU.1 (5,35). It has been reported that IL-1β gene contains several SNPs, including −511 T/C, −1464 C/G, −2023 C/A, −3737 G/A, −31 T/A, +289 C/T, and +3953 C/T, and may be associated with altered expression of the cytokine (20,50,51).

Interestingly, both IL-18 and IL-1β receptors contain a toll-IL-1 receptor (TIR) domain, which is common with TIR domain of TLRs and, hence, the intracellular signaling pathways of TLRs and IL-8/IL-1β receptors are similar and associated with activation of several TFs such as nuclear factor kappa-light-chain-enhancer of activated B cells, interferon regulatory factor 7, and activator protein-1 in the signaling adaptor myeloid differentiation primary response 88-dependent manner (16). It appears that IL-18/IL-1β interactions with their corresponded receptors lead to activation of intracellular signaling pathways, which have synergistic effects with TLR signaling pathways (4). The functions of IL-18 and IL-1β can be regulated by IL-18 binding protein and IL-1 receptor antagonist, respectively (10,14).

IL-18 and IL-1β Gene Polymorphisms in CHB Infection

Due to the crucial roles played by IL-18 and IL-1β in the induction of immune responses and consequently inflammation, the genetic variations in the IL-18 and IL-1β genes may be associated with hepatitis B and its complications.

IL-18 Gene Polymorphisms and CHB

The investigations regarding IL-18 gene polymorphisms had different results. Accordingly, a study by Jiang et al. revealed that −137 G allele and GG genotype are associated with progression of CHB and lower IL-18 serum levels, respectively, in a Chinese population (28). Jiang et al., in 2014, also confirmed the results and reported that the GG genotype and G allele of −137 polymorphism were associated with CHB and lower production of IL-18 in the Chinese population (29). Another study on the Chinese population revealed that the GC and CC genotypes of the polymorphism in the −137 region were associated with an increased risk of HCC in CHB patients (37). Bao et al. demonstrated that the GC genotype and C allele of the polymorphism in the −137 region were significantly associated with decreased risk of HCC in HBV-infected patients (6). Another study showed that the GG genotype and G allele of the −137 polymorphism were associated with severity of necroinflammatory activity and liver fibrosis (17). The protective roles played by −137 C allele against HBV infection have been demonstrated by Zhang et al. (56). Another study on an Indian population showed that either genotype GC at position −137 or genotype CC at position −607 were higher in CHB patients who suffered from HCC and LC than healthy controls (31). Another study by Zhang et al. showed that the −137 C allele may protect the patients against CHB, while −607 AA genotype is closely linked to suppressing HBV-DNA replication (55). Migita et al. also reported that −607 AA genotype and −137 C allele were significantly higher in the inactive CHB patients when compared to the chronic progressive liver patients (42). Association of −607 AA genotype with the progression of CHB has also been documented by Hirankarn et al. (23). The higher copy number of HBV-DNA in CHB patients carrying −607 AA genotype was reported previously (56). Zhang et al. also reported that AA genotype and A allele at −607 promoter region are significantly associated with the morbidity of either HBV-related HCC or CHB patients (57). In contrast, Li et al. demonstrated that AA genotype and A allele at −607 promoter region are potentially associated with the resistance to CHB (38). However, they showed that the genotype and allele were not significantly different between the HBV-related HCC and CHB patients (p > 0.05) (38). The investigations on other IL-18 gene polymorphisms are rare. Accordingly, Kim et al. reported that −148 C, +8925 G, and +13925 C alleles in the IL-18 gene were associated with the presence of HCC in CHB patients (34). Another investigation demonstrated that the −148 C, +8925 G, and the +13925 C alleles were closely associated with HBV clearance (13).

In contrast to the studies, Zhu et al. reported that the polymorphisms at −137 and −607 promoter region of IL-18 were not associated with the development of HCC in CHB patients (59). No association of the polymorphisms at −607 promoter region of IL-18 with HCC risk in CHB patients was reported by Lau et al. (37). Bao et al. also revealed that the polymorphisms at −607 promoter region were not associated with HCC in an HBV-infected Chinese population (6). The −137 and −607 promoter polymorphisms in the IL-18 gene also were not associated with HBV recurrence in the liver transplant patients (39).

Due to the studies, the polymorphisms within −137 region of IL-18 gene strongly associated with HCC development, except the study by Zhu et al. (59), and interestingly, all of the study, except the studies by Jiang et al. (28,29), demonstrated that C allele, which is frequent in the GC and CC genotypes carrying patients, may be considered a factor that participates in the development of HCC. However, the studies demonstrated that the allele and genotypes are significantly associated with HBV eradication and inhibition of CHB progression. Meanwhile, the roles of the allele are controversial. The studies regarding the associations of the polymorphisms within −607 region are also controversies; however, most investigations proved the roles played by AA genotype in the progression or inhibition of CHB and its complications (23,42,57). Table 1 summarizes the investigations regarding IL-18 gene polymorphisms in HBV-infected patients and related diseases.

Table 1.

IL-18 Gene Polymorphisms in Hepatitis B Virus-Infected Patients

Gene	Polymorphisms	Hepatitis B-associated functions	References
IL-18	−137 G allele and GG genotype	Progression of CHB	(28)
	−137 G allele and GG genotype	Progression of CHB	(29)
	−137 GC and CC genotypes	Increased risk of HCC	(37)
	−137 GC genotype and C allele	Decreased risk of HCC	(6)
	−137 GG genotype and G allele	Severity of liver fibrosis	(17)
	−137 C allele	Protective roles against HBV infection	(56)
	−137 GC genotype	Increased risk of HCC and liver cirrhosis	(31)
	−137 C allele	Protection against CHB	(55)
	−137 C allele	Decreased risk of chronic progressive liver disease	(42)
	−137 genotypes and alleles	No association with development of HCC	(59)
	−137 genotypes and alleles	No association with HBV recurrence	(39)
	−607 AA genotype	Suppressing HBV-DNA replication	(55)
	−607 CC genotype	Increased risk of HCC and liver cirrhosis	(31)
	−607 AA genotype	Decreased risk of chronic progressive liver disease	(42)
	−607 AA genotype	Progression of CHB	(23)
	−607 AA genotype	Increased copy number of HBV-DNA	(56)
	−607 AA genotype and A allele	Increased morbidity of CHB and HCC patients	(57)
	−607 AA genotype and A allele	Resistance to CHB	(38)
	−607 genotypes and alleles	No association with development of HCC	(59)
	−607 genotypes and alleles	No association with development of HCC	(37)
	−607 genotypes and alleles	No association with development of HCC	(6)
	−607 genotypes and alleles	No association with HBV recurrence	(39)
	−148 C allele	Increased risk of HCC	(34)
	+8925 G allele	Increased risk of HCC	(34)
	+13925 C allele	Increased risk of HCC	(34)
	−148 C allele	HBV clearance	(13)
	+8925 G allele	HBV clearance	(13)
	+13925 C allele	HBV clearance	(13)

CHB, chronic hepatitis B; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

IL-1β Gene Polymorphisms and CHB

In contrast to IL-18 gene polymorphisms, investigations regarding the roles played by IL-1β gene polymorphisms in CHB have no significant pattern. Accordingly, investigations regarding the polymorphisms within −31 and +3953 positions of IL-1β gene revealed that the T/T genotype and T allele, respectively, are factors at most risk for the development of CHB, HCC, and LC. For instance, Migita et al. reported that IL-1β −31 TT and TC genotypes were significantly higher in CHB patients who suffered from LC than those without LC (41). Chen et al. proved the association of IL-1β −31 TT genotype with increased risks of HCC in CHB patients (12). A study by Javan et al. revealed that the TT genotype of IL-1β −1 polymorphism is significantly higher in CHB patients when compared to healthy controls (26). A study by Javan et al. also revealed that the CT genotype at IL-1β +3953 position was significantly higher in CHB patients when compared to healthy controls (26). IL-1β +3953 T allele increased 1.5 times the risk of CHB in a Turkish population (9). The positive correlation between IL-1β gene polymorphism at +3953 position with increased response to hepatitis B vaccination and also susceptibility to ultraviolet B has been demonstrated previously (48,53).

Investigations, except the study by Javan et al. (26), regarding the roles of IL-1β −511 polymorphisms in CHB progression and its complications revealed that the CC genotype is the most important risk factor for the development of CHB, progression of HCC as well as LC, and decreased responses to the HBV vaccination. For example, an investigation showed that IL-1β −511 CC genotype was strongly higher in CHB patients when compared to the healthy controls (8). Chan et al. revealed that CT genotype at −511 position was associated with higher sustained response to antiviral treatment than CC genotype (11). Another study revealed that, although IL-1β −511 polymorphism was not associated with CHB in a Chinese population, CC genotype was associated with increased replication of HBV in CHB patients (54). Hirankarn et al. also confirmed the results and reported that IL-1β −511 CC genotype and C allele are significantly associated with increased production of IL-1β, and increased susceptibility to HCC in CHB patients (22).

Kim et al. also reported that IL-1β −2023 C and +289 C alleles were significantly associated with persistence of HBV infections and increased risk for the presence of HCC, respectively (33).

Thus, it seems that the polymorphisms within the IL-1β gene are more related to CHB and its complications than IL-18 gene. Nevertheless, two limited studies were unable to find these relationships. Borekci et al., revealed that IL-1β −31 and −511 polymorphisms were not associated with CHB in a Turkish population (9). No association of IL-1β −511 polymorphism with HCC progression has been demonstrated by Saxena et al. (46). Bei et al. also evaluated another polymorphism at IL-1β −1464 CG position and were unable to find a significant association with increased risks of HCC among HBV-infected Chinese population (7). Table 2 shows the polymorphisms within IL-1β gene in HBV-infected patients.

Table 2.

IL-1β Gene Polymorphisms in Hepatitis B Virus-Infected Patients

Gene	Polymorphisms	Hepatitis B-associated functions	References
IL-1β	−31 TT and TC genotypes	Increased risk of liver cirrhosis	(41)
	−31 TT genotype	Increased risk of HCC	(12)
	−31 TT genotype	Increased risk of CHB	(26)
	−31 polymorphism	No association with CHB and HCC	(9)
	+3953 CT genotype	Increased risk of CHB	(26)
	+3953 T allele	Increased risk of CHB	(9)
	+3953 polymorphism	Increased response to hepatitis B vaccination	(48,53)
	−511 CC genotype	Increased risk of CHB	(8)
	−511 CT genotype	Higher responses to anti-viral treatment	(11)
	−511 CC genotype	Increased replication of HBV	(54)
	−511 CC genotype and C allele	Increased risk of HCC	(22)
	−511 polymorphism	No association with CHB and HCC	(26)
	−511 polymorphism	No association with CHB and HCC	(9)
	−511 polymorphism	No association with HCC	(46)
	−1464 (C→G) polymorphism	No association with HCC	(7)

Conclusion

Taken together, IL-18 gene polymorphism relationships with CHB, LC, and HCC are controversial, while IL-1β gene polymorphisms have significant correlations with the disorders. Due to the fact that most investigations on IL-18 gene polymorphisms were performed on the Chinese population and the investigations on the other ethnics are low or absent, hence, it may be proposed that more studies need to be performed to shed light on the molecular mechanisms of the IL-18 gene polymorphisms in the pathogenesis of CHB and its complications. However, based on the results presented in this study, IL-1β gene polymorphisms are the risk factors for progression of CHB, LC, and HCC. In addition, it has been documented that gender can be considered an important factor for the association of IL-1β gene polymorphisms with LC in CHB patients (18). Thus, it may be hypothesized that gender-related studies may be considered for future investigations regarding IL-1β and IL-18 gene polymorphisms in CHB patients. Moreover, the studies on other polymorphisms within IL-1β and IL-18 genes are too low to achieve a final conclusion regarding the roles of gene polymorphisms with CHB patients. In addition, it may be worthy to evaluate the polymorphisms in the inflammasomes, ASC and caspase-1 as the upstream molecules of IL-1β and IL-18, and their relationship with CHB and its related LC and HCC.

Footnotes

Acknowledgment

This article has been supported by Rafsanjan University of Medical Sciences.

Author Disclosure Statement

No competing financial interests exist.

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