Hepatitis C virus and disrupted interferon signaling promote lymphoproliferation via type II CD95 and interleukins.
OBJECTIVE
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.


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.


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.


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.
Machida
Keigo
K
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Tsukiyama-Kohara
Kyoko
K
Sekiguch
Satoshi
S
Seike
Eiji
E
Tóne
Shigenobu
S
Hayashi
Yukiko
Y
Tobita
Yoshimi
Y
Kasama
Yuri
Y
Shimizu
Masumi
M
Takahashi
Hidemi
H
Taya
Chyoji
C
Yonekawa
Hiromichi
H
Tanaka
Nobuyuki
N
Kohara
Michinori
M
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000276:immunology / Q000473:pathology; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008223:Lymphoma / Q000276:immunology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D013997:Time Factors; D014758:Viral Core Proteins / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
C087035:E1 protein, Hepatitis C virus; D050856:Interferon Regulatory Factor-1; D007376:Interleukin-2; D007378:Interleukins; C494258:Irf1 protein, mouse; C097010:NS2 protein, Hepatitis C virus; D019253:Proto-Oncogene Proteins c-bcl-2; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D019014:fas Receptor; D016753:Interleukin-10; C091015:glycoprotein E2, Hepatitis C virus; D018664:Interleukin-12; D020169:Caspases