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1.
J Virol ; 88(18): 10412-20, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24872585

RESUMEN

UNLABELLED: The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHB) are poorly defined. Innate immune responses play an important role in reducing HBV replication and pathogenesis. HBV has developed numerous mechanisms to escape these responses, including the production of the secreted hepatitis B e antigen (HBeAg), which has been shown to regulate antiviral toll-like receptor (TLR) and interleukin-1 (IL-1) signaling. IL-18 is a related cytokine that inhibits HBV replication in hepatoma cell lines and in the liver through the induction of gamma interferon (IFN-γ) by NK cells and T cells. We hypothesized that HBV or HBV proteins inhibit IFN-γ expression by NK cells as an accessory immunomodulatory function. We show that HBeAg protein inhibits the NF-κB pathway and thereby downregulates NK cell IFN-γ expression. Additionally, IFN-γ expression was significantly inhibited by exposure to serum from individuals with HBeAg-positive but not HBeAg-negative chronic HBV infection. Further, we show that the HBeAg protein suppresses IL-18-mediated NF-κB signaling in NK and hepatoma cells via modulation of the NF-κB pathway. Together, these findings show that the HBeAg inhibits IL-18 signaling and IFN-γ expression, which may play an important role in the establishment and/or maintenance of persistent HBV infection. IMPORTANCE: It is becoming increasingly apparent that NK cells play a role in the establishment and/or maintenance of chronic hepatitis B infection. The secreted HBeAg is an important regulator of innate and adaptive immune responses. We now show that the HBeAg downregulates NK cell-mediated IFN-γ production and IL-18 signaling, which may contribute to the establishment of infection and/or viral persistence. Our findings build on previous studies showing that the HBeAg also suppresses the TLR and IL-1 signaling pathways, suggesting that this viral protein is a key regulator of antiviral innate immune responses.


Asunto(s)
Regulación hacia Abajo , Antígenos e de la Hepatitis B/metabolismo , Virus de la Hepatitis B/metabolismo , Hepatitis B/genética , Interferón gamma/genética , Interleucina-18/metabolismo , Adulto , Células Cultivadas , Femenino , Hepatitis B/inmunología , Hepatitis B/virología , Antígenos e de la Hepatitis B/genética , Virus de la Hepatitis B/genética , Interacciones Huésped-Patógeno , Humanos , Interferón gamma/inmunología , Interleucina-18/genética , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Transducción de Señal , Adulto Joven
2.
J Biol Chem ; 276(2): 1133-7, 2001 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-11050102

RESUMEN

Previously it was shown that the HHV-8-encoded chemokine receptor ORF74 shows considerable agonist-independent, constitutive activity giving rise to oncogenic transformation (Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., and Cesarman, E. (1997) Nature 385, 347-350). In this study we report that a second viral-encoded chemokine receptor, the human cytomegalovirus-encoded US28, also efficiently signals in an agonist-independent manner. Transient expression of US28 in COS-7 cells leads to the constitutive activation of phospholipase C and NF-kappaB signaling via G(q/11) protein-dependent pathways. Whereas phospholipase C activation is mediated via Galpha(q/11) subunits, the activation of NF-kappaB strongly depends on betagamma subunits with a preference for the beta(2)gamma(1) dimer. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and MCP-1 (monocyte chemotactic protein-1) act as neutral antagonists at US28, whereas the CX(3)C chemokine fractalkine acts as a partial inverse agonist with IC(50) values of 1-5 nm. Our data suggest that a high level of constitutive activity might be a more general characteristic of viral G protein-coupled receptors and that human cytomegalovirus might exploit this G protein-coupled receptor property to modulate the homeostasis of infected cells via the early gene product US28.


Asunto(s)
Quimiocinas CX3C , Citomegalovirus/fisiología , Glicoproteínas , Receptores de Quimiocina/fisiología , Proteínas Virales/fisiología , Animales , Células COS , Quimiocina CX3CL1 , Quimiocinas CXC/fisiología , Chlorocebus aethiops , Citomegalovirus/genética , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Fosfatos de Inositol/metabolismo , Proteínas de la Membrana/fisiología , FN-kappa B/metabolismo , Receptores de Quimiocina/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Transfección , Fosfolipasas de Tipo C/metabolismo , Proteínas Virales/genética
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