Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of aggregation chimaeras and X-linked polymorphisms strongly suggest that liver tumours are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the gut mucosa and epidermis, where a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, since these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumours, hepatocellular carcinoma and cholangiocarcinoma, is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, although it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover, the existence of bipotential hepatic progenitor cells, along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Cell proliferation at the time of carcinogen exposure is pivotal for 'fixing' any genotoxic injury into a heritable form, thus any proliferative cell in the liver can be susceptible to neoplastic transformation. Hepatocytes are implicated in many instances of hepatocellular carcinoma, direct injury to the biliary epithelium implicates cholangiocytes in some cases of cholangiocarcinoma, while hepatic progenitor cell/oval cell activation accompanies many instances of liver damage irrespective of aetiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that hepatic progenitor cell proliferation may be merely a bystander effect of this toxicity. An in-depth discussion of causes of cancer in the liver is beyond the scope of this review, but infectious agents (e.g. hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus), but also in causing chronic inflammation (hepatitis C and B viruses). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors and DNA-damaging agents (reactive oxygen and nitrogen species--produced to fight infection), will lead to permanent genetic changes in proliferating cells. Up-regulation of the transcription factor NF-kappaB in transformed hepatocytes, through the paracrine action of TNF-alpha from neighbouring endothelia and inflammatory cells, may be critical for tumour progression given the mitogenic and antiapoptotic properties of proteins encoded by many of NF-kappaB's target genes.
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PMID:Liver cancer: the role of stem cells. 1630 Jun 53

NF-kappaB activation plays a crucial role in anti-apoptotic responses in response to the apoptotic signaling during tumor necrosis factor (TNF)-alpha stimulation. TNF-alpha induces apoptosis sensitive to the hepatitis B virus (HBV) infected cells, despite sustained NF-kappaB activation. Our results indicate that the HBV infection induces sustained NF-kappaB activation, in a manner similar to the TNF-alpha stimulation. However, these effects are not merely combined. Computational simulations show that the level of form of the IKK complex activated by phosphorylation (IKK-p) affects the dynamic pattern of NF-kappaB activation during TNF-alpha stimulation in the following ways: (i) the initial level of IKK-p determines the incremental change in IKK-p at the same level of TNF-alpha stimulation, (ii) the incremental change in IKK-p determines the amplitudes of active NF-kappaB oscillation, and (iii) the steady state level of IKK-p after the incremental change determines the period of active NF-kappaB oscillation. Based on experiments, we observed that the initial level of IKK-p was upregulated and the active NF-kappaB oscillation showed smaller amplitudes for a shorter period in HepG2.2.15 cells (HBV-producing cells) during TNF-alpha stimulation, as was indicated by the computational simulations. Furthermore, we found that during TNF-alpha stimulation, NF-kappaB-regulated anti-apoptotic genes were upregulated in HepG2 cells but were downregulated in HepG2.2.15 cells. Based on the previously mentioned results, we can conclude that the IKK-p-level changes induced by HBV infection modulate the dynamic pattern of active NF-kappaB and thereby could affect NF-kappaB-regulated anti-apoptotic gene expressions. Finally, we postulate that the sensitive apoptotic response of HBV-infected cells to TNF-alpha stimulation is governed by the dynamic patterns of active NF-kappaB based on IKK-p level changes.
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PMID:The influence of the signal dynamics of activated form of IKK on NF-kappaB and anti-apoptotic gene expressions: a systems biology approach. 1641 45

Immunogenic peptide-based vaccines can raise significant cellular immune responses. Although cytotoxic T lymphocytes (CTL) peptide epitopes are generally poor immunogens, heat shock protein 70 from Mycobacterium tuberculosis (TBhsp70) can overcome this problem since it is a potent adjuvant that links innate and adaptive immune responses. Our goal is to use TBhsp70 as an adjuvant for development of therapeutic vaccines for chronic Hepatitis B virus infection (HBV). To this end, we genetically fused the HBV core 18-27 peptide (HBcAg((18-27))) as a CTL epitope to the C-terminus of TBhsp70 and expressed the resulting protein in methylotropic yeast Pichia pastoris GS115. At the same time, the TBhsp70-HBcAg((18-27)) peptide complex was reconstituted in vitro. We investigated whether TBhsp70-peptide complex and TBhsp70-peptide fusion protein could generate antigen specific CTL responses in vitro. Dendritic cells (DC) from HLA-A2(+) chronic HBV infection and healthy control pulsed with two vaccines were studied phenotypically by FACS analyses and functionally by cytokine release, and HBV-specific CTL response. Our results demonstrate that two vaccines can activate DC of chronic HBV infection and healthy control by upregulation CD40 and CD86, high production of IL-12p70 and TNF-alpha. Furthermore, autologous T cells with DC stimulated by two vaccines can produce IFN-gamma and generate HBV-specific CTL response. However, capacity for CTL response and cytokines production from HBV infections remained inferior to that of healthy controls. Thus, the strategy of utilizing TBhsp70 may provide a novel design for the development of prophylactic and therapeutic vaccines.
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PMID:Novel vaccines for the treatment of chronic HBV infection based on mycobacterial heat shock protein 70. 1644 13

Infections are a major adverse effect during the treatment with anti-TNF-alpha. While exclusion of any bacterial infection and screening for tuberculosis are mandatory before initiating a therapy with anti-TNF-alpha-antibodies, there are no guidelines whether to screen for or how to deal with chronic viral infections such as hepatitis B. In this case report, we have described a patient with Crohn's disease who developed subfulminant hepatitis B after the fourth infusion of infliximab due to an unrecognized HBs-antigen carrier state. He recovered completely after lamivudine therapy was started, but this severe adverse event could have been prevented if screening for HBV and pre-emptive therapy with lamivudine would have been started prior to infliximab. We therefore strongly argue in favor of extended screening recommendations for infectious diseases including viral infections before considering a therapy with infliximab.
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PMID:Subfulminant hepatitis B after infliximab in Crohn's disease: need for HBV-screening? 1652 Dec 31

It is very important to understand the mechanism of immune tolerance or hyporesponsiveness in hepatitis B virus (HBV) infected individuals so as to treat HBV. In the present study we detected the cellular immune states of chronic asymptomatic HBV carriers and tried to probe their mechanisms and the strategy to promote their specific cellular immune responses. HBV non-specific antigens and specific antigens alone or with IL-12 were used to stimulate peripheral blood mononuclear cells (PBMCs) from the HBV carriers and healthy controls for evaluation of cytokine responses. IFN-gamma, TNF-alpha, IL-12P40 and IL-12P70 in the supernatants were assayed by ELISA, and the frequency as well as phenotype of IFN-gamma-producing cells were detected by ELISpot and FACS, respectively. The results showed that PBMCs from the HBV carriers secreted less IFN-gamma and IL-12 than those from the healthy controls. Exogenous IL-12 in combination with HBV specific antigens promoted PBMCs from the HBV carriers to secret more IFN-gamma by augmenting the frequency of CD8(+) IFN-gamma(+) T cells. Further studies indicated that majority of IFN-gamma-producing cells belonged to central memory CD8(+) T cells. Thus, our study provided the evidence that insufficient production of IL-12 is involved in the mechanism of hyporesponsiveness in HBV infected persons. The addition of IL-12 plus HBV specific antigen into cultures of PBMCs could restore their specific cellular immune responses. These data may have an important implication in the possibility of designing effective vaccine against HBV infection.
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PMID:IL-12 promotes HBV-specific central memory CD8+ T cell responses by PBMCs from chronic hepatitis B virus carriers. 1738 5

Cell-mediated immune responses to BCG vaccine were evaluated in 7-month-old infants vaccinated with intradermal combined BCG and Hepatitis B or intradermal BCG and intramuscular Hepatitis B at birth. Peripheral blood mononuclear cell cultures from both groups showed CD4(+), CD8(+) and remarkable gammadelta(+) T cell BCG-specific proliferation, without significant differences. Also, IL-10, IL-12, IFN-gamma and TNF-alpha concentrations in culture supernatants, measured by ELISA, were similar. The results suggested that the combined BCG and Hepatitis B vaccine was as immunogenic as BCG separated from Hepatitis B vaccine.
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PMID:Robust gammadelta+ T cell expansion in infants immunized at birth with BCG vaccine. 1764 59

Chemokines are classified in four distinct groups as CXC, CC, CX3C and C, depending on the presence or absence of a motif called ELR (Arg-Leu-Glu) before the first cysteine residue in their structure. CXC chemokines are also subdivided into ELR+ and ELR-. Increasing evidence has indicated the existence of a chemokine network in the liver which is involved in both physiological responses and, under certain circumstances, pathological and repair processes following hepatic injury. The CXC chemokines play a major role in both these processes, and much attention has been focused on their therapeutic applications to liver disease. The aim of this study was to examine the response of cultured hepatocytes to exogenous inflammatory cytokines (TNF-alpha and IFN-gamma) regarding expression of IP-10 and growth regulatory oncogen (Gro) chemokines. In this study we employed western and northern analysis to measure chemokines at the level of protein and mRNA by hepatocytes in response to pro-inflammatory cytokines. We found that, the pro-inflammatory cytokines, TNF-alpha and IFN-gamma, selectively stimulated expression of IP-10 but were without effect on Gro. This confirms a potential direct involvement of these cytokines in chemokine production by hepatocytes. Thus, IFN-gamma and TNF-alpha may play a role in hepatic injury and inflammation and produce some of their biological effects by localized induction of chemokines by hepatocytes. Given the similarity to an acute phase response, we were able to show that IFN-gamma and TNF-alpha mimicked the effects of cell isolation and culture on induction of IP-10 expression. Further, evidence for linkages between IFN- gamma and TNF- alpha and liver injuries is seen in hepatitis C and hepatitis B in which increased levels of TNF- alpha and its soluble receptor were reported.
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PMID:Expression of IP-10 chemokine is regulated by pro-inflammatory cytokines in cultured hepatocytes. 1789 31

Considerable evidence suggests that host genetic factor play an important role in the pathogenesis and clinical outcome of chronic hepatitis B virus (HBV) infection in several ethic groups. Association study was performed included 150 chronic HBV patients, 100 resolved hepatitis B and 150 healthy individuals with similar ethic background. Interestingly, human leucocyte antigen (HLA)-DR13 show a strong association with the clearance of HBV [odds ratio (OR) = 0.04, 95% confidence interval (CI) = 0.00-0.26, corrected P-value (P(c)) = 0.0008] similar to reports from several ethic groups. TNF-alpha promoter polymorphisms (-863, -308 and -238) were also analysed. Only -863 C allele was found to be significantly decreased in chronic HBV patients compared with healthy control (P(c) = 0.03, OR = 0.54, 95% CI = 0.35-0.84 respectively). This -863C allele was not in linkage disequilibrium with HLA-DR13 suggesting that other genetic markers linked with -863C might influence clearance of chronic HBV infection in Thai. When stratified chronic HBV patients into patients without hepatocellular carcinoma (HCC) and with HCC, the -863 A allele was significantly increased in the HCC group compared to healthy control (P(c) = 0.003, OR = 2.61, 95% CI = 1.49-4.60). Haplotype analysis (-863/-308/-238) revealed that the homozygosity of the haplotype (CGG/CGG) was a protective marker for HCC (OR = 0.37, 95% CI = 0.17-0.79, P(c) = 0.02). One can propose that carriers of -863A genotype are associated with increased levels of TNF-alpha in the liver in response to HBV infection and induce hapatocyte damage that may finally lead to HCC development. Additional study is needed to validate these finding and to further explore the genetic pathogenesis of HBV infection.
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PMID:Association of HLA-DRB1*13 and TNF-alpha gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. 1807 Feb 87

Hepatitis B virus has been linked to the pathogenesis and carcinogenesis of hepatocellular carcinoma. Components of viruses have been identified within pathological specimens of hepatocellular carcinoma tissue. We characterized the in vitro response of human normal liver cells (L-02 cells) to components of infectious agents related to toll-like receptors. Immortalized human normal liver cells (L-02 cells) exhibited increased proliferation in response to exposure to CpG DNA. This molecule is a well-characterized surrogate for DNA viruses, which are common in the liver. Our experiments show that L-02 cells and some hepatoma cell lines such as HepG2, HuH7, Hep3B, express TLR 9 (CpG-specific). CpG DNA, HBV DNA, DNA of HBV middle envelope protein (MP) containing a number of CpG, supernatant of HepG2.2.15 (HepG2 cells transfected HBV) excreting HBV DNA and extraction of nucleic acids from HepG2.2.15 supernatant can all activate NF-kappaB. In addition, L-02 cells were less susceptible to TNF-alpha-induced apoptosis as measured by Annexin V-FITC staining when stimulated with CpG. mRNA of DNA methyltransferase 1 (DNMT-1) and BCL-2 was increased when L-02 cells were stimulated with CpG DNA. Our study has identified a possible novel mechanism that indicates how CpG DNA of HBV DNA may contribute to the malignant transformation of benign liver cells.
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PMID:Hepatitis B virus DNA-induced carcinogenesis of human normal liver cells by virtue of nonmethylated CpG DNA. 1928 92

Toll-like receptors (TLRs) are part of the innate immune system. They recognize some protein, lipid, and nucleic structures that are common in microorganisms such as bacteria and viruses but not present in the human body. The stimulation of TLRs initiates the activation of an intracellular signaling network which results in the secretion of proinflammatory cytokines, mainly type I interferons, TNF-alpha, and IL-6. TLR2, TLR3, TLR4, TLR8, and TLR9 take part in the recognition of viral infections, four of them by discerning nucleic acids, with TLR3 recognizing dsRNA, TLR7 and TLR8-ssRNA, and TLR9-DNA. The role of TLRs in the development of infections and other inflammatory states, neoplasms, and autoimmune disorders is under investigation. The importance of TLRs in the natural course of hepatitis B and C and in the treatment of these diseases are the subject of particular interest. Attempts to apply TLR7 and TLR9 agonists in the treatment of chronic hepatitis type C are underway. A better understanding of the role of TLRs in the complex immunological phenomena accompanying viral hepatitis might put the therapeutic possibilities in these infections into a new perspective.
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PMID:[Toll-like receptors in viral hepatitis]. 1964 51


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