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Hepatitis C virus and disrupted interferon signaling promote lymphoproliferation via type II CD95 and interleukins.
- Source :
-
Gastroenterology [Gastroenterology] 2009 Jul; Vol. 137 (1), pp. 285-96, 296.e1-11. Date of Electronic Publication: 2009 Apr 09. - Publication Year :
- 2009
-
Abstract
- Background & Aims: The molecular mechanisms of lymphoproliferation associated with the disruption of interferon (IFN) signaling and chronic hepatitis C virus (HCV) infection are poorly understood. Lymphomas are extrahepatic manifestations of HCV infection; we sought to clarify the molecular mechanisms of these processes.<br />Methods: We established interferon regulatory factor-1-null (irf-1(-/-)) mice with inducible and persistent expression of HCV structural proteins (irf-1/CN2 mice). All the mice (n = 900) were observed for at least 600 days after Cre/loxP switching. Histologic analyses, as well as analyses of lymphoproliferation, sensitivity to Fas-induced apoptosis, colony formation, and cytokine production, were performed. Proteins associated with these processes were also assessed.<br />Results: Irf-1/CN2 mice had extremely high incidences of lymphomas and lymphoproliferative disorders and displayed increased mortality. Disruption of irf-1 reduced the sensitivity to Fas-induced apoptosis and decreased the levels of caspases-3/7 and caspase-9 messenger RNA species and enzymatic activities. Furthermore, the irf-1/CN2 mice showed decreased activation of caspases-3/7 and caspase-9 and increased levels of interleukin (IL)-2, IL-10, and Bcl-2, as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes. IL-2 and IL-10 were induced by the HCV core protein in splenocytes.<br />Conclusions: Disruption of IFN signaling resulted in development of lymphoma, indicating that differential signaling occurs in lymphocytes compared with liver. This mouse model, in which HCV expression and disruption of IFN signaling synergize to promote lymphoproliferation, will be an important tool for the development of therapeutic agents that target the lymphoproliferative pathway.
- Subjects :
- Age Factors
Animals
Apoptosis
B-Lymphocytes immunology
B-Lymphocytes virology
Caspases metabolism
Cell Proliferation
Disease Models, Animal
Female
Hepacivirus genetics
Hepatitis C, Chronic immunology
Hepatitis C, Chronic pathology
Interferon Regulatory Factor-1 deficiency
Interferon Regulatory Factor-1 genetics
Interferon Regulatory Factor-1 metabolism
Interleukin-10 metabolism
Interleukin-12 metabolism
Interleukin-2 metabolism
Lymphoma immunology
Lymphoma virology
Lymphoproliferative Disorders pathology
Male
Mice
Mice, Knockout
Mice, Transgenic
Proto-Oncogene Proteins c-bcl-2 metabolism
Spleen immunology
Spleen virology
T-Lymphocytes immunology
T-Lymphocytes virology
Time Factors
Viral Core Proteins metabolism
Viral Envelope Proteins metabolism
Viral Nonstructural Proteins metabolism
Viral Proteins genetics
Hepacivirus metabolism
Hepatitis C, Chronic complications
Interleukins metabolism
Lymphoproliferative Disorders immunology
Lymphoproliferative Disorders virology
Signal Transduction
Viral Proteins metabolism
fas Receptor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 137
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 19362089
- Full Text :
- https://doi.org/10.1053/j.gastro.2009.03.061