Hepatitis C Virus and Disrupted Interferon Signaling Promote Lymphoproliferation via Type II CD95 and Interleukins

Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Gastroenterology (Impact Factor: 13.93). 04/2009; 137(1):285-96, 296.e1-11. DOI: 10.1053/j.gastro.2009.03.061
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Conditional transgene activation of the HCV cDNA (core, E1, E2, and NS2) protects mice from Fas-mediated lethal acute liver failure, by inhibiting cytochrome c release from mitochondria [11]. Persistent HCV protein expression is established by targeted disruption ISRN Hematology of interferon regulatory factor-1 (irf-1), and high incidences of lymphoproliferative disorders are noted in irf-1 −/− CN2 mice [12]. Previously, transgenic mice that expressed the HCV core protein were established using a promoter derived from hepatitis B virus [13], whereas mice that expressed structural or complete viral proteins were established using promoters derived from the albumin gene [14]. "
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