Dual effects of interleukin-18: inhibiting hepatitis B virus replication in HepG2.2.15 cells and promoting hepatoma cells metastasis

Zhang, Yijuan; Li, Yunbo; Ma, Yifan; Liu, Shuhui; She, Yuanbin; Zhao, Peng; Jing, Ming-Zhen; Han, Tao; Yan, Chao; Wu, Zhao; Gao, Jinrong; Ye, Linbai

doi:10.1152/ajpgi.00058.2011

Cited by 37 publications

(36 citation statements)

References 21 publications

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“…IL18 has prometastatic effects in melanoma patients and may promote clinical aggressiveness of human myeloid leukemia (13). IL18 also promoted hepatoma cell metastasis and migration (25). We found that IL18 promoted the proliferation and invasion of pancreatic cancer cells in vitro and in vivo but had no effect on apoptosis, drug resistance, or stem cell-like properties in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 71%

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

Guo

Jiang

et al. 2016

Clinical Cancer Research

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Purpose: We sought to find new immune-based treatments for pancreatic cancer.Experimental Design: We detected IL18 expression in plasma and specimens from patients with pancreatic cancer. We then investigated whether IL18 had a therapeutic effect for pancreatic cancer in vitro and in vivo and any underlying mechanisms.Results: Higher plasma IL18 was associated with longer overall survival (OS), but higher IL18 in pancreatic cancer tissues was associated with shorter OS and increased invasion and metastasis. Recombinant IL18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral blood and lymph nodes. However, IL18 promoted the proliferation and invasion of pancreatic cancer cells, in vitro and in vivo, through the NF-kB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-kB inhibitor, we were able to prevent the procancerous effects of IL18 and prolong the survival time of the mice.Conclusions: IL18 has both cancer-promoting and cancersuppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-kB pathway inhibitor, IL18 improved survival in a murine pancreatic cancer model. Our study implies the possibility of a combinational immunotherapy that uses IL18 and targets NF-kB pathway.

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Section: Discussionmentioning

confidence: 71%

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

Guo

Jiang

et al. 2016

Clinical Cancer Research

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“…This inhibitory effect by IL-18 could be rescued by the administration of BAY11-7082, an inhibitor of transcription factor NF-κB. Furthermore, it was confirmed that expression of IL-18/IL-18R were remarkably up regulated in hepatocellular carcinoma (HCC) liver cancer tissue specimens, suggesting that IL-18 is involved in HCC metastasis in addition to its suppressive effect on HBV replication [11,12].…”

Section: Introductionmentioning

confidence: 82%

Association of Gene Polymorphisms and Serum Levels of IL-18 with the Susceptibility to Infection with Hepatitis B Virus

Hasan¹,

Naif²

2017

J Infect Dis Med

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Background: IL-18 gene polymorphisms is shown to be involved in various diseases. This study examines the influence of IL-18 gene polymorphism on the natural course of Hepatitis B Virus (HBV) infection together with the impact of serum levels in Iraqi population for the first time.Methods: A total of 55 patients and similar numbers of healthy controls were recruited in this study. Gene polymorphisms at positions -607C/A and -137G/C of IL-18 were examined using the allele-specific polymerase chain reaction (PCR). Serum levels of IL-18 were determined by an ELISA kit.Results: Three genotypes of IL-18-607C/A (rs1946518) were observed and distributed variably in both patients and controls: CC, CA, and AA with frequencies 41 (82%), 3 (6%), and 6 (12%), in patients and in 44 (88%), 5 (10%), and 1 (2%) in the controls, respectively. The homozygous -607AA mutant genotype, A and C allele frequencies were significantly higher (p=0.043) in patients than the healthy control group (A: 15% and 7%, p=0.04 and C: 85% and 93%, p=0.04, respectively) (OR=2.3445, 95%CI=0.9121-6.0269). The effect of treatment against HBV on genotype and allele frequencies compared with untreated patients revealed that CC and AA genotypes were significantly higher (p=0.04) in treated than untreated patients mirrored results obtained in patients and controls. Three genotypes of IL-18-137G/C (rs187238) were observed in both patients and healthy controls: GG, GC, and CC that appeared in 30 (60%), 18 (36%), and 2 (4%) of HBV infected patients and in 32 (64%), 16 (32%), and 2 (4%) of the control group, respectively. No significant genotype or alleles (G and C) frequencies observed between patients and controls (OR=0.863, 95%CI=0.4485-1.7516). Serum levels of IL-18 was found to be significantly higher in HBV-infected patients compared to the control group. IL-18 levels decreased significantly by various genotypes of both SNPs and this was consistently associated with the mutant genotypes of -137 SNP.Conclusion: IL-18-607AA mutant genotype and C and A alleles were significantly associated with a high risk to HBV infection in Iraqi population, however, the -137 genotypes had no clear impact on the disease and its role as a protective factor needs further investigation. In contrast, the downregulation of the circulating levels of IL-18 in patients was associated with the -137 and -607 mutant genotypes.

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“…Since IL-18-stimulated IFN-␥ has direct antiviral effects against HBV and activation of IL-18 signaling decreases HBV replication in hepatocytes (14), it is not surprising that HBV evolved mechanisms to regulate IL-18 signaling and IFN-␥ expression. HBV utilizes numerous mechanisms to regulate other innate immunity signaling pathways, including HBeAg and precore protein-mediated regulation of TLR2 (5, 6) and IL-1␤ (7), with the latter sharing a number of salient features with IL-18 signaling (33).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which HBV establishes and maintains chronic infection are still to be resolved. However, recent findings that NK cell-driven IFN-␥ responses are lower in CHB patients with high HBV viral loads (16) and that upregulation of IL-1 or the related IL-18 signaling inhibits HBV replication in hepatocytes (4,14) suggests that regulation of IL-18 is one mechanism by which HBV facilitates persistence. This is further supported by our findings that suppression of IFN-␥ expression by NK cells is directly mediated both by factors present in serum from HBeAgpositive CHB patients and by the HBeAg protein itself.…”

Section: Discussionmentioning

confidence: 99%

“…Murine studies have shown that IL-18 (11) inhibits HBV replication through induction of IFN-␥ (12,13), which directly inhibits the HBV life cycle at the pre-and posttranslational level. In vitro studies have recently shown that, similar to IL-1 (4), overexpression of IL-18 inhibits HBV replication in a hepatoma cell line (14), although the mechanism for this inhibition is unclear, as hepatocytes do not produce IFN-␥.…”

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confidence: 99%

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Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen

Jegaskanda

Ahn

Skinner

et al. 2014

J Virol

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The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHBT he mechanisms by which hepatitis B virus (HBV) establishes and maintains persistent infection are not fully understood. It has become increasingly apparent that innate immune response via the effector functions of a range of cell types, including Kupffer cells, natural killer (NK) cells, and hepatocytes, play an important role in controlling HBV infection (1-3). Our group has previously shown that stimulation of the interleukin-1 (IL-1) and toll-like receptor 2 (TLR2) signaling pathways inhibits HBV replication in vitro (4). In turn, we and others have shown that the hepatitis B e antigen (HBeAg; p17) downregulates antiviral TLR2-and IL-1␤-mediated responses (5-7). HBeAg is secreted as a nonparticulate form of the hepatitis B virus (HBV) nucleocapsid protein (hepatitis B core antigen [HBcAg]; p21), which is processed from larger precore polyproteins (p25 and p22) (8). Although not required for HBV replication, the precore protein and HBeAg are critical for the establishment of persistent infection. The HBV precore protein and HBeAg are important regulators of innate and adaptive immune responses that contribute to the establishment and/or maintenance of persistent infection.IL-18 is a proinflammatory cytokine synthesized and secreted by mononuclear cells, including Kupffer cells. In the presence of the necessary costimulatory ligands, such as IL-12 (9), IL-18 stimulates IFN-␥ production by NK cells, T cells, dendritic cells (DCs), and B cells. IL-18 signaling is activated following the interaction of two receptors: the alpha-receptor, IL-18R1, and the beta-receptor, AcPL, both of which dimerize following ligand binding to the alpha component, initiating signal transduction by AcPL (10). Murine studies have shown that IL-18 (11) inhibits HBV replication through induction of IFN-␥ (12, 13), which directly inhibits the HBV life cycle at the pre-and posttranslational level. In vitro studies have recently shown that, similar to IL-1 (4), overexpression of IL-18 inhibits HBV replication in a hepatoma cell line (14), although the mechanism for this inhibition is unclear, as hepatocytes do not produce IFN-␥.NK cells are lymphocytes that eliminate virus-infected cells by both direct cytolysis and the production of several antiviral cytokines, including IFN-␥. HBV infection stimulates NK cells, most likely via the activation of DCs and macrophages that produce and chemokines, including CXCR3 (15). NK cells

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Dual effects of interleukin-18: inhibiting hepatitis B virus replication in HepG2.2.15 cells and promoting hepatoma cells metastasis

Cited by 37 publications

References 21 publications

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

Association of Gene Polymorphisms and Serum Levels of IL-18 with the Susceptibility to Infection with Hepatitis B Virus

Downregulation of Interleukin-18-Mediated Cell Signaling and Interferon Gamma Expression by the Hepatitis B Virus e Antigen

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