Mechanistic study of interaction between IL-22 and HCV core protein in the development of hepatocellular carcinoma among liver transplant recipients

Resham, Saleha; Saalim, Muhammad; Manzoor, Sobia; Ahmad, Hassam; Bangash, Tariq Ali; Latif, Amer; Jaleel, Shahla

doi:10.1016/j.micpath.2020.104071

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…To treat HCV-associated liver cancer, we proposed a bivalent DNA vaccine against HCV-associated liver cancer based on telomerase reverse transcriptase (TERT) and HCV core, and designed and optimized each of the components. HCV core is a highly conserved viral protein [ 16 ], expressed in all HCV infected cells, including those in the liver tumors [ 17 , 18 , 19 ]. We previously showed that plasmids inducing high level of expression of HCV core were less immunogenic than low-expressing vectors, even those missing the Kozak sequence [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

“…HCV core is highly conserved [ 16 ]. Furthermore, it is expressed by all HCV infected liver cells, also malignant, and promotes transformation [ 17 , 18 , 19 , 20 ]. Taken together, this supports the use of HCV core in a therapeutic vaccine to prevent morbidity and mortality related to chronic HCV infection, including liver cancer.…”

Section: Introductionmentioning

confidence: 99%

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Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

et al. 2021

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Chronic HCV infection and associated liver cancer impose a heavy burden on the healthcare system. Direct acting antivirals eliminate HCV, unless it is drug resistant, and partially reverse liver disease, but they cannot cure HCV-related cancer. A possible remedy could be a multi-component immunotherapeutic vaccine targeting both HCV-infected and malignant cells, but also those not infected with HCV. To meet this need we developed a two-component DNA vaccine based on the highly conserved core protein of HCV to target HCV-infected cells, and a renowned tumor-associated antigen telomerase reverse transcriptase (TERT) based on the rat TERT, to target malignant cells. Their synthetic genes were expression-optimized, and HCV core was truncated after aa 152 (Core152opt) to delete the domain interfering with immunogenicity. Core152opt and TERT DNA were highly immunogenic in BALB/c mice, inducing IFN-γ/IL-2/TNF-α response of CD4+ and CD8+ T cells. Additionally, DNA-immunization with TERT enhanced cellular immune response against luciferase encoded by a co-delivered plasmid (Luc DNA). However, DNA-immunization with Core152opt and TERT mix resulted in abrogation of immune response against both components. A loss of bioluminescence signal after co-delivery of TERT and Luc DNA into mice indicated that TERT affects the in vivo expression of luciferase directed by the immediate early cytomegalovirus and interferon-β promoters. Panel of mutant TERT variants was created and tested for their expression effects. TERT with deleted N-terminal nucleoli localization signal and mutations abrogating telomerase activity still suppressed the IFN-β driven Luc expression, while the inactivated reverse transcriptase domain of TERT and its analogue, enzymatically active HIV-1 reverse transcriptase, exerted only weak suppressive effects, implying that suppression relied on the presence of the full-length/nearly full-length TERT, but not its enzymatic activity. The effect(s) could be due to interference of the ectopically expressed xenogeneic rat TERT with biogenesis of mRNA, ribosomes and protein translation in murine cells, affecting the expression of immunogens. HCV core can aggravate this effect, leading to early apoptosis of co-expressing cells, preventing the induction of immune response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

et al. 2021

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“…IL-22 was involved in hepatofibrosis (HF) and cirrhosis associated with HCV infection. On one hand, IL-22 can activate the innate immunity of liver, promote the expression of pro-inflammatory factors, promote the proliferation, migration and tissue regeneration of liver cells, and reduce the apoptosis of liver cells ( 58 – 60 ). Hence, it may be an effective target for the treatment of liver fibrosis and HCC.…”

Section: The Roles Of Th22 Cells In Human Viral Diseasesmentioning

confidence: 99%

“…HCV core protein is critical to drive the transformation of normal hepatocytes into cancer cells. Suppressor of cytokine Signaling 3 (SOCS-3) proteins can cause the dysfunction of IL-22-mediated hepatocyte regeneration, and HCV core protein and SOCS-3 are highly expressed in patients with liver cirrhosis and HCC ( 58 ). These findings indicate that Th22 cells and associated molecules play a crucial role in the pathogenesis of HCV infection.…”

Section: The Roles Of Th22 Cells In Human Viral Diseasesmentioning

confidence: 99%

Role of Th22 Cells in Human Viral Diseases

et al. 2021

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Naive CD4+ T cells can differentiate into different cell subsets after receiving antigen stimulation, which secrete corresponding characteristic cytokines and thereby exert biological effects in various diseases. Th22 cells, a novel subset of CD4+ T cells, are different from Th1, Th2, Th17, and Treg cell subsets, which have been discovered in recent years. They can express CCR4, CCR6, and CCR10 molecules and secrete IL-22, IL-13, and TNF-α. They are not able to secrete IL-17, IL-4, and interferon-γ (IFN-γ). IL-22 is considered as a major effector molecule of Th22 cells whose functions and mechanisms of regulating cell differentiation have been constantly improved. In this review, we provide an overview of the origin, differentiation of Th22 cells. Moreover, we also describe the interrelationships between Th22 cells and Th17, Th1, and Th2 cells. Additionally, the role of Th22 cells were discussed in human diseases with virus infection, which will provide novel insight for the prevention and treatment of viral infection in human.

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“…Concerning HCC, many studies detected an upregulation of IL-22 in the serum of patients suffering from HCC [119][120][121][122]. Likewise, an increased IL-22 production could be measured in the tissue of HCC in comparison to cirrhotic or healthy tissue controls [121][122][123][124]. Moreover, it was found that IL-22 levels were equally correlated to clinical stages of HCC [119,121].…”

Section: Liver Regenerationmentioning

confidence: 99%

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

et al. 2021

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The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient’s immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by TH22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4+ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.

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Mechanistic study of interaction between IL-22 and HCV core protein in the development of hepatocellular carcinoma among liver transplant recipients

Cited by 8 publications

References 26 publications

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

Role of Th22 Cells in Human Viral Diseases

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

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