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: 16.72). 04/2009; 137(1):285-96, 296.e1-11. DOI: 10.1053/j.gastro.2009.03.061
Source: PubMed


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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    • "Focusing on animal models, core transgenic mice developed lymphoma with high frequency [89]. In another transgenic model, the expression of the HCV core in the context of all structural proteins and in a irf −/− background, was associated with the development of lymphoid disorders including frank lymphoma [90]. More recently, the expression of the whole HCV genome in the B-cell compartment resulted in a high prevalence of diffuse large B-cell lymphoma [91]. "
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    ABSTRACT: The relationship between Hepatitis C Virus (HCV) infection and immunosuppression is complex and multifaceted. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This generally occurs during the immunosuppression state, and not at the reconstitution of the host response after immunosuppressive therapy discontinuation. The field of immunosuppression and HCV infection is complicated both by the different outcome observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. This review will briefly outline the current knowledge about the pathogenesis of both hepatic and extrahepatic HCV-related disorders and the principal available data concerning HCV infection in a condition of impairment of the immune system. Attention will be especially focused on some conditions - liver or kidney transplantation, the use of biologic drugs and cancer chemotherapy - for which more abundant and interesting data exist.
    Full-text · Article · Aug 2012 · Journal of Translational Medicine
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    • "The core mRNA was shown in the enlarged lymph nodes of the transgenic mice which developed lymphoma. In another transgenic model, where the IFN signaling was disrupted, the inducible and persistent expression of the HCV core in the context of all structural proteins was associated with the development of lymphoid disorders including frank lymphoma, suggesting a synergistic action of the viral proteins with IFN signaling impairment in promoting lymphomagenesis [46]. "
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    ABSTRACT: Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury--potentially evolving to cirrhosis and hepatocellular carcinoma--but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.
    Full-text · Article · Jul 2012 · Clinical and Developmental Immunology
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    • "Zuckerman et al. [47] reported a significantly higher incidence of Bcl2 gene translocation in peripheral blood cells in cases with HCV-seropositive hepatitis, compared with HCV-negative controls (p < 0.01). Machida et al. [48] demonstrated that disruption of interferon regulatory factor 1 in HCV-infected mice increased serum IL-2 and Bcl2 expression in lymphocytes, and induced a high incidence of B-cell lymphoma. As well as inducing anti-apoptotic Bcl2 and transcription factors such as Bcl6, IL-2 may activate cytokine signaling via CD25 (IL2αR) in HCV-infected B cells [49]. "
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    ABSTRACT: Sixty-four cases of malignant lymphoma involving the liver were examined. Of these, 20 cases were histologically confirmed to be primary hepatic B-cell lymphoma. Twelve of these 20 cases were diffuse large B-cell lymphoma (DLBCL) and eight cases were mucosa-associated lymphoid tissue (MALT) lymphoma. Of the 12 cases of DLBCL, six were immunohistologically positive for CD10 and/or Bcl6 (indicating a germinal center phenotype), six were positive for Bcl2, and five were positive for CD25. Eight of the 12 DLBCL cases (66.7%) and two of the eight MALT lymphoma cases (25%) had serum anti-hepatitis C virus (HCV) antibodies and HCV RNA. The incidence of HCV infection was significantly higher in the hepatic DLBCL cases than in systemic intravascular large B-cell cases with liver involvement (one of 11 cases, 9.1%) and T/NK-cell lymphoma cases (one of 19 cases, 5.3%) (p < 0.01 for both). Two hepatic DLBCL cases (16.7%) had rheumatoid arthritis treated with methotrexate, and four MALT lymphoma cases (50%) had Sjögren's syndrome, primary biliary cirrhosis, or autoimmune hepatitis; one case in each of these two groups was complicated by chronic HCV-seropositive hepatitis. Although primary hepatic lymphoma is rare, persistent inflammatory processes associated with HCV infection or autoimmune disease may play independent roles in the lymphomagenesis of hepatic B cells.
    Full-text · Article · Mar 2012 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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