Tue, 2013-04-16 22:08 | 
Background: Infections due to hepatitis B (HBV) and hepatitis C (HCV) virus are a worldwide public health problem (1-3). More than 2 billion people and 170 million people have been infected from HBV and HCV, respectively (WHO, www.who.int και CDC www.cdc.gov).
Both viruses cause immune-mediated necroinflammatory liver damage and both are characterized by high propensity to chronicity.
Innate and adaptive immune responses against both viruses have been shown to be crucial in controlling viral replication. IFN-γ has been demonstrated to have a paramount role in controlling HBV and HCV specific CD4+ and CD8+ T cell responses (4-7). p38 Mitogen Activated Protein Kinase (MAPK), one of the most important molecules of intracellular signaling, has a coordinating role in the production of IFN-γ. Specifically, p38 MAPK is involved in the regulation of immune responses through cytokine production, including IFN-γ and TNF-α and though control of T lymphocyte differentiation (8-9). Studies in Huh4 cell lines transfected with HCV subgenomic replicon have shown the fundamental role of p38 MAPK activation in the IFN-α mediated HCV-specific T-cell immune responses (10-11). Similarly, studies in Huh7 cells supporting HBV replication demonstrated suppression of viral replication as a result of inhibition of p38 MAPK, indicating a possible role of p38 MAPK in the outcome of HBV infection (12).
Aim – Methods: The aim of the present study is to assess the contribution of intracellular signaling mechanisms and specifically of p38 MAPK at different phases of the natural history of HBV and HCV infections and also during antiviral treatment of both infections.
Experiments are going to be performed in peripheral mononuclear cells (PBMCs) from patients with HBV and HCV infection alongside with healthy individuals. p38 MAPK activation is going to be measured at baseline and after culture with non specific stimuli (arsenite) and cytokines (IL-12, IL-2, IL-18). Activation of p38 MAPK is going to be evaluated by flow cytometry using fluorophore-conjugated antibodies. Cytokine production (IFN-γ and IL-10) is going to be evaluated by ELISpot and ELISA in PBMC cultures from patients and healthy controls at baseline and after adding SB203580, which is a specific inhibitor of p38 MAPK.
References:
1. Dalekos, G.N., et al., Prevalence of viral markers among refugees from southern Albania: increased incidence of infection with hepatitis A, B and D viruses. Eur J Gastroenterol Hepatol, 1995. 7(6): p. 553-8.
2. Gatselis, N.K., et al., Risk factors associated with HCV infection in semi-rural areas of central Greece. Eur J Intern Med, 2007. 18(1): p. 48-55.
3. Stefos, A., et al., Descriptive epidemiology of chronic hepatitis B by using data from a hepatitis registry in Central Greece. Eur J Intern Med, 2009. 20(1): p. 35-43.
4. Rehermann, B. and M. Nascimbeni, Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol, 2005. 5(3): p. 215-29.
5. Hadziyannis, S.J., et al., Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med, 2005. 352(26): p. 2673-81.
6. Rigopoulou, E.I., et al., Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology, 2005. 42(5): p. 1028-36.
7. Rigopoulou, E.I., et al., Blocking of interleukin-10 receptor--a novel approach to stimulate T-helper cell type 1 responses to hepatitis C virus. Clin Immunol, 2005. 117(1): p. 57-64
8. Saklatvala, J., The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol, 2004. 4(4): p. 372-7.
9. Mavropoulos, A., et al., Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells. Blood, 2005. 105(1): p. 282-8.
10. Ishida, H., et al., Involvement of p38 signaling pathway in interferon-alpha-mediated antiviral activity toward hepatitis C virus. Biochem Biophys Res Commun, 2004. 321(3): p. 722-7.
11. Sundstrom, S., et al., Hepatitis C virus core protein induces an anergic state characterized by decreased interleukin-2 production and perturbation of mitogen-activated protein kinase responses. J Virol, 2005. 79(4): p. 2230-9.
12. Chang, W.W., et al., Suppression of p38 mitogen-activated protein kinase inhibits hepatitis B virus replication in human hepatoma cell: the antiviral role of nitric oxide. J Viral Hepat, 2008. 15(7): p. 490-7.
