A recombinant adenovirus encoding hepatitis C virus core and E1 proteins protects mice against cytokine-induced liver damage.
Hepatitis C virus (HCV) infection has a strong tendency to evolve to chronicity despite up-regulation of proapoptotic cytokines in the inflamed liver. The mechanisms responsible for persistent viral replication in this inflammatory environment are obscure. It is conceivable that viral replication would be facilitated if the infected hepatocytes are rendered resistant to cytokine-induced cytotoxicity. In this study, we investigated if an adenovirus encoding HCV core and E1 (RAdCE1) could reduce liver cell injury in different in vivo models of cytokine-mediated hepatotoxicity in mice. We show that RAdCE1 markedly attenuates hepatocellular apoptosis and the increase in serum transaminase levels after concanavalin A (con A) challenge. This protective effect is accompanied by an inhibition of nuclear translocation of nuclear factor kappaB (NF-kappaB); reduced expression of inducible nitric oxide synthase (iNOS); decreased hepatic messenger RNA levels of chemokines macrophage inflammatory protein 2 (MIP-2), monocyte chemoattractant protein 1 (MCP-1), and interferon-inducible protein 10 (IP-10); and abrogation of liver leukocyte infiltration. RAdCE1 also causes a reduction in serum transaminase levels and inhibits hepatocellular apoptosis in mice given tumor necrosis factor (TNF)-alpha plus D-galactosamine. In conclusion, HCV structural antigens can protect liver cells against the proapoptotic effects of proinflammatory cytokines. The antiapoptotic status of infected liver cells may represent a mechanism favoring viral persistence. Our findings also suggest that, in chronic hepatitis C, the burden of hepatocellular damage mainly affects noninfected liver cells.
Lasarte
Juan José
JJ
FIMA (Fundación para la Investigación Médica Aplicada), Department of Internal Medicine, Medical School and University Clinic, University of Navarra, Pamplona, Spain. jjlasarte@unav.es
Sarobe
Pablo
P
Boya
Patricia
P
Casares
Noelia
N
Arribillaga
Laura
L
de Cerio
Ascensión López-Díaz
AL
Gorraiz
Marta
M
Borrás-Cuesta
Francisco
F
Prieto
Jesús
J
D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D003208:Concanavalin A; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D004338:Drug Combinations; D005260:Female; D005688:Galactosamine; D015870:Gene Expression / Q000502:physiology*; D016174:Hepacivirus / Q000235:genetics*; D008107:Liver Diseases / Q000209:etiology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011995:Recombination, Genetic; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000235:genetics*
D016207:Cytokines; D004338:Drug Combinations; C087035:E1 protein, Hepatitis C virus; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; D003208:Concanavalin A; D005688:Galactosamine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse