| First Author | Brenndörfer ED | Year | 2012 |
| Journal | Gut | Volume | 61 |
| Issue | 4 | Pages | 589-96 |
| PubMed ID | 21813471 | Mgi Jnum | J:194449 |
| Mgi Id | MGI:5473778 | Doi | 10.1136/gut.2010.232116 |
| Citation | Brenndorfer ED, et al. (2012) Hepatitis C virus non-structural 3/4A protein interferes with intrahepatic interferon-gamma production. Gut 61(4):589-96 |
| abstractText | BACKGROUND: The non-structural (NS) 3/4A protease/helicase of the hepatitis C virus is known to modulate signalling pathways in the infected hepatocyte by cleaving CARD adaptor inducing IFNbeta (Cardif), T-cell protein tyrosine phosphatase (TC-PTP) and TIR domain-containing adaptor inducing IFNbeta (TRIF), but the effects of NS3/4A in vivo still remain unclear. AIM: To investigate the influence of NS3/4A on intracellular and intercellular signalling in vivo by analysing the intrahepatic inflammatory response of naive, lipopolysaccharide (LPS)/D-galactosamine (D-galN) or tumour necrosis factor-alpha (TNFalpha)/D-galN-treated NS3/4A-transgenic (Tg) mice. METHODS: The intrahepatic immunity of naive and LPS/D-galN- or TNFalpha/D-galN-treated NS3/4A-Tg mice was determined using western blot, ELISA, real-time PCR, flow cytometry and survival monitoring. The injection of cytokines or antibodies against signalling components was performed to analyse the relevance of the respective pathways for the investigated issues. A Tg mouse lineage expressing an inactivated NS3/4A protease (NS3/4A(Ile1073Ala)-Tgs) was generated to examine if protective effects were NS3/4A protease dependent. RESULTS: The activation of hepatic signal transducer and activator of transcription 1 and 2 was impaired in NS3/4A-Tg mice after treatment with LPS/D-galN or TNFalpha/D-galN. This was paralleled by a reduction in hepatic interferon-gamma (IFNgamma). Reconstitution of IFNgamma reverted the resistance to LPS/TNFalpha in NS3/4A-Tg mice. Subsequently, blocking IFNgamma in vivo rendered wild-type mice resistant against treatment with LPS/TNFalpha. A new Tg mouse expressing an inactivated NS3/4A protease had the same phenotype as wild-type mice with respect to hepatic IFNgamma levels and sensitivity to LPS/d-galN. Finally, the chemokine profile was altered in the NS3/4A-Tg mice towards an anti-inflammatory state, which helps to explain the altered immune cell subsets and reduction in hepatic IFNgamma production. CONCLUSIONS: Our data demonstrate that the NS3/4A protease reduces the intrahepatic production of IFNgamma and alters TNFalpha-mediated effects, thereby impairing the hepatic inflammatory response. This may contribute to viral persistence. |
