Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent Manner

Li, Yang-Xia; Ren, Yan; Fu, Haijing; Zou, Ling; Yang, Ying; Chen, Zhi

doi:10.1371/journal.pone.0159089

Cited by 20 publications

(17 citation statements)

References 38 publications

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“…After a literature review, we found that our VZV IL-6 data were most similar to a description of elevated IL-6 following hepatitis B infection [30]. During hepatitis B infection, dysregulated production of the viral surface proteins leads to their retention in the ER with subsequent ER stress.…”

Section: Discussionsupporting

confidence: 77%

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

Jarosinski

Carpenter

Buckingham

et al. 2018

Open Forum Infectious Diseases

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BackgroundThe infectious cycle of varicella-zoster virus (VZV) after reactivation from the dorsal root ganglia includes replication and assembly of complete enveloped virions in the human skin to cause the characteristic herpes zoster (shingles).MethodsTo pursue studies of innate immunity to VZV infection, we have adapted a fetal skin organ culture model to a human neonatal foreskin explant model.ResultsAbundant expression of VZV IE62, gE, and gC was visualized by confocal microscopy while numerous enveloped virions were observed by electron microscopy in infected skin organ cultures. Microarray experiments demonstrated that the patterns of upregulated transcripts differed between VZV-infected cells and VZV-infected skin explants. One result stood out, namely a >30-fold elevated interleukin (IL)-6 level in the infected skin explant that was not present in the infected monolayer culture. The IL-6 results in the polyermase chain reaction (PCR) assay were reproduced by quantitative PCR testing with newly designed primers. To determine if increased transcription was accompanied by increased IL-6 expression, we quantitated the levels of IL-6 protein in the explant media at increasing intervals after infection. We found a statistically significant increase in IL-6 protein levels secreted into the media from VZV-infected skin explants as compared with mock-infected explants.ConclusionsThe cellular stress response to VZV infection in neonatal skin explants included highly elevated levels of IL-6 transcription and expression. This skin organ model could be adapted to other viruses with a skin tropism, such as herpes simplex virus.

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Section: Discussionsupporting

confidence: 77%

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

Jarosinski

Carpenter

Buckingham

et al. 2018

Open Forum Infectious Diseases

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“…Many members of this family are reported to be involved in the HBV infection. IL-6 expression is upregulated by hepatitis B virus core antigen and middle S antigen via p38 MAPK/NF-κB pathways 19 20 . Meanwhile, serum IL-23 level in HBeAg-positive HBV infection patients before therapy could be used to predict the therapeutic response to interferon (IFN) 21 .…”

Section: Discussionmentioning

confidence: 99%

Interleukin-35 Level Is Reduced in Patients with Chronic Hepatitis B Virus Infection

et al. 2018

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Backgrounds: As one of the major public health problems, the hepatitis B virus (HBV) infection would activate the immune system. The outcome of HBV infection was affect significantly by the interactions between HBV and host immune response. Interleukins play important role in anti-viral immunity. Here we investigated the role of interleukin-35 (IL-35) in chronic HBV infection patients.Methods/Results: Serum IL-35 in 72 chronic hepatitis B virus infection patients and 41 healthy control subjects were analyzed by ELISA assay. The mRNA level of IL-35 in PBMCs was determined by RT-qPCR. In this study, we found that both protein and mRNA levels of IL-35 were significantly decreased in chronic HBV patients compared to the healthy controls. Furthermore, the statistical analysis found that serum IL-35 was significantly associated with HBV DNA (P =0.0158), ALT (P =0.0003), AST (P =0.0216), TB (P =0.0270) and AFP (P =0.0369). Importantly, correlation analysis also found that serum IL-35 level was negatively correlated with HBV DNA copies, ALT, AST, TB and AFP. Meanwhile, IL-35 treatment inhibited the level of HBV DNA, HBsAg and HBeAg in HepAD38 cells.Conclusion: Our study identified that IL-35 may be a novel marker associated with HBV infection and hepatocytes injury. These data suggested the potential use of IL-35 in the HBV treatment.

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“…Although environmental factors may play an important role in the pathogenesis and course of pemphigus, the contribution of viral infections to the disease remains unclear ( 72 ). Nonetheless, it has been reported that a hepatitis B virus envelope protein is capable of activating the p38 MAPK and NFĸB pathways in an ER stress-dependent manner ( 73 ), being therefore an example of how viral factors could directly contribute to a connected ER stress induction and p38 MAPK activation. Altogether, by adding ER stress to the understanding of pemphigus pathogenesis, an entirely new set of hypotheses and connections can be made in the context of the signaling pathways activated in the disease.…”

Section: The Emerging Role Of Er Stress In Pemphigusmentioning

confidence: 99%

Crosstalk between Signaling Pathways in Pemphigus: A Role for Endoplasmic Reticulum Stress in p38 Mitogen-Activated Protein Kinase Activation?

et al. 2017

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Pemphigus consists of a group of chronic blistering skin diseases mediated by autoantibodies (autoAbs). The dogma that pemphigus is caused by keratinocyte dissociation (acantholysis) as a distinctive and direct consequence of the presence of autoAb targeting two main proteins of the desmosome—desmoglein (DSG) 1 and/or DSG3—has been put to the test. Several outside-in signaling events elicited by pemphigus autoAb in keratinocytes have been described, among which stands out p38 mitogen-activated protein kinase (p38 MAPK) engagement and its apoptotic effect on keratinocytes. The role of apoptosis in the disease is, however, debatable, to an extent that it may not be a determinant event for the occurrence of acantholysis. Also, it has been verified that compromised DSG trans-interaction does not lead to keratinocyte dissociation when p38 MAPK is inhibited. These examples of conflicting results have been followed by recent work revealing an important role for endoplasmic reticulum (ER) stress in pemphigus’ pathogenesis. ER stress is known to activate the p38 MAPK pathway, and vice versa. However, this relationship has not yet been studied in the context of activated signaling pathways in pemphigus. Therefore, by reviewing and hypothetically connecting the role(s) of ER stress and p38 MAPK pathway in pemphigus, we highlight the importance of elucidating the crosstalk between all activated signaling pathways, which may in turn contribute for a better understanding of the role of apoptosis in the disease and a better management of this life-threatening condition.

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Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent Manner

Cited by 20 publications

References 38 publications

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

Interleukin-35 Level Is Reduced in Patients with Chronic Hepatitis B Virus Infection

Crosstalk between Signaling Pathways in Pemphigus: A Role for Endoplasmic Reticulum Stress in p38 Mitogen-Activated Protein Kinase Activation?

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