scholarly journals Lack of Tumor Necrosis Factor Alpha Induces Impaired Proliferation of Hepatitis B Virus-Specific Cytotoxic T Lymphocytes

2003 ◽  
Vol 77 (4) ◽  
pp. 2469-2476 ◽  
Author(s):  
Senji Kasahara ◽  
Kazuki Ando ◽  
Kuniaki Saito ◽  
Kenji Sekikawa ◽  
Hiroyasu Ito ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Cytotoxic T Lymphocytes ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
B Virus ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Recent studies have shown that tumor necrosis factor alpha (TNF-α) plays critical roles in not only viral clearance but also lymphoid tissue development and stem cell differentiation. In this study, we attempted to induce hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) by immunization of TNF-α knockout (TNF-α−/−) mice with HBsAg-encoding plasmid DNA. An immunization with the HBV plasmid failed to induce CTL responses in TNF-α−/− mice, although CTLs were readily induced in wild-type mice by the same protocol. Weak CTL responses were produced in TNF-α−/− mice after two sessions of immunization with the HBV plasmid; however, TNF-α was required to maintain the responses of these CTL lines to in vitro stimulation and, even then, the responses were lost after 3 weeks. Interestingly, a limiting dilution of a CTL line showed that HBV-specific CTL clones with high specific cytotoxicity were present in TNF-α−/− mice, but these clones again failed to proliferate for more than 3 weeks. Furthermore, since exogenously added TNF-α enhanced the proliferation of a TNF-α−/− clone but suppressed that of a TNF-α+/+ clone in vitro, TNF-α also has a direct effect on the proliferation of CTLs. In conclusion, TNF-α is essential rather than important for the proliferation of HBV-specific CTLs both in vivo and in vitro and this effect is not only due to the activation of dendritic cells but is also induced by the direct effect on CTLs.

scholarly journals Tumor Necrosis Factor Alpha Inhibition of Hepatitis B Virus Replication Involves Disruption of Capsid Integrity through Activation of NF-κB

2003 ◽  
Vol 77 (7) ◽  
pp. 4033-4042 ◽  
Author(s):  
Michael Biermer ◽  
Robyn Puro ◽  
Robert J. Schneider
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Hepatitis B ◽  
Virus Replication ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
B Virus ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Chronic infection by hepatitis B virus results from an inability to clear the virus, which is associated with liver disease and liver cancer. Tumor necrosis factor alpha (TNF-α) is associated with noncytopathic clearance of hepatitis B virus in animal models. Here we demonstrate that the nuclear factor κB (NF-κB) signaling pathway is a central mediator of inhibition of hepatitis B virus by TNF-α and we describe the molecular mechanism. TNF-α is shown to suppress hepatitis B virus DNA replication without cell killing by disrupting the formation or stability of cytoplasmic viral capsids through a pathway requiring the NF-κB-activating inhibitor of κB kinase complex IKK-α/β and active transcription factor NF-κB. Hepatitis B virus replication could also be inhibited and viral capsid formation could be disrupted in the absence of TNF-α solely by overexpression of IKK-α/β or strong activation of NF-κB. In contrast, inhibition of NF-κB signaling stimulated viral replication, demonstrating that HBV replication is both positively and negatively regulated by the level of activity of the NF-κB pathway. Studies are presented that exclude the possibility that HBV inhibition by NF-κB is carried out by secondary production of gamma interferon or alpha/beta interferon. These results identify a novel mechanism for noncytopathic suppression of hepatitis B virus replication that is mediated by the NF-κB signaling pathway and activated by TNF-α.

scholarly journals Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

2002 ◽  
Vol 70 (12) ◽  
pp. 6628-6637 ◽  
Author(s):  
Christopher J. Papasian ◽  
Richard Silverstein ◽  
Jian Jun Gao ◽  
David M. Bamberger ◽  
David C. Morrison
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Potential Contribution ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The murine d-galactosamine (d-gal) model of tumor necrosis factor alpha (TNF-α) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-α to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. d-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-α antibody protected d-gal-treated, E. faecalis-infected mice, implicating TNF-α in the lethal response to E. faecalis infection in d-gal-treated mice. Circulating TNF-α was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-α were detected within 3 h, suggesting that localized TNF-α production contributed to the lethal response to E. faecalis infection in d-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-α response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-α. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-α response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-α production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-α production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.

scholarly journals Mechanism of Rapid Transcriptional Induction of Tumor Necrosis Factor Alpha-Responsive Genes by NF-κB

2002 ◽  
Vol 22 (18) ◽  
pp. 6354-6362 ◽  
Author(s):  
Elena Ainbinder ◽  
Merav Revach ◽  
Orit Wolstein ◽  
Sandra Moshonov ◽  
Noam Diamant ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
In Vitro Transcription ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Transcriptional Induction ◽  
Necrosis Factor

ABSTRACT NF-κB induces the expression of genes involved in immune response, apoptosis, inflammation, and the cell cycle. Certain NF-κB-responsive genes are activated rapidly after the cell is stimulated by cytokines and other extracellular signals. However, the mechanism by which these genes are activated is not entirely understood. Here we report that even though NF-κB interacts directly with TAFIIs, induction of NF-κB by tumor necrosis factor alpha (TNF-α) does not enhance TFIID recruitment and preinitiation complex formation on some NF-κB-responsive promoters. These promoters are bound by the transcription apparatus prior to TNF-α stimulus. Using the immediate-early TNF-α-responsive gene A20 as a prototype promoter, we found that the constitutive association of the general transcription apparatus is mediated by Sp1 and that this is crucial for rapid transcriptional induction by NF-κB. In vitro transcription assays confirmed that NF-κB plays a postinitiation role since it enhances the transcription reinitiation rate whereas Sp1 is required for the initiation step. Thus, the consecutive effects of Sp1 and NF-κB on the transcription process underlie the mechanism of their synergy and allow rapid transcriptional induction in response to cytokines.

Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus–specific immune response

Hepatology ◽  
2007 ◽  
Vol 46 (3) ◽  
pp. 699-705 ◽  
Author(s):  
Jeroen N. Stoop ◽  
Andrea M. Woltman ◽  
Paula J. Biesta ◽  
Johannes G. Kusters ◽  
Ernst J. Kuipers ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Suppressive Effect ◽  
Necrosis Factor Alpha ◽  
B Virus ◽  
Factor Alpha ◽  
Necrosis Factor
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