fax: ++49-761-270-33720
Viral Hepatitis
CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-jun N terminal kinase activation independent from the interferon pathway†‡
Article first published online: 7 JAN 2013
DOI: 10.1002/hep.25966
Copyright © 2012 American Association for the Study of Liver Diseases
Additional Information
How to Cite
Rau, S. J., Hildt, E., Himmelsbach, K., Thimme, R., Wakita, T., Blum, H. E. and Fischer, R. (2013), CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-jun N terminal kinase activation independent from the interferon pathway. Hepatology, 57: 23–36. doi: 10.1002/hep.25966
- †
Potential conflict of interest: Nothing to report.
- ‡
Supported by Hepato-Regio-Net (Europäischer Fonds für regionale Entwicklung des Oberrheins) and Deutsche Forschungsgemeinschaft (Fi 801/2-1), Germany.
- §
fax: ++49-761-270-33720
Publication History
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 19 JUL 2012 05:45AM EST
- Manuscript Accepted: 1 JUL 2012
- Manuscript Received: 2 DEC 2011
References
- 1, . Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol 2007; 25: 71-99.
- 2, , , , , , et al. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 2009; 136: 1391-1401.
- 3, , , , , , et al. Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. HEPATOLOGY 2002; 35: 694-703.
- 4, , , , , . Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 2009; 229: 152-172.
- 5
- 6
- 7, , , , , , et al. Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunol 2007; 8: 57-63.
- 8, , , , , . Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. J Biol Chem 1998; 273: 9344-9351.
- 9, , , , , , et al. The stress kinase mitogen-activated protein kinase kinase (MKK)7 is a negative regulator of antigen receptor and growth factor receptor-induced proliferation in hematopoietic cells. J Exp Med 2001; 194: 757-768.
- 10, , , , , , et al. Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. J Exp Med 1997; 186: 941-953.
- 11, . Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Immunity 1997; 6: 379-387.
- 12, , , . IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev 2008; 19: 383-394.
- 13, , , , , . Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology 2007; 132: 1925-1936.
- 14, , , , , , et al. Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways. HEPATOLOGY 2008; 47: 1462-1472.
- 15, , , , , , et al. CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL. J Immunol 2008; 181: 1001-1011.
- 16. CD40 ligand therapy of lymphoma patients. J Clin Oncol 2001; 19: 4351-4353.
- 17
- 18, , , , , , et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 2007; 25: 876-883.
- 19, , , , , , et al. Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner. J Immunol 2008; 181: 4926-4935.
- 20, , , , , , et al. Caspase activation is required for antiviral treatment response in chronic hepatitis C virus infection. HEPATOLOGY 2006; 43: 1311-1316.
- 21, , , , , . CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 1999; 189: 441-446.
- 22, , , , , , et al. CD40 expression in HCV-associated chronic liver diseases. Int J Mol Med 2006; 18: 559-563.
- 23, , , , , , et al. Expression of functional CD40 in human hepatocellular carcinoma. HEPATOLOGY 1999; 30: 920-926.
- 24, , , , , . CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis. HEPATOLOGY 2005; 42: 372-380.
- 25, , , , , , et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005; 11: 791-796.
- 26, , , . Sequences in the 5′ nontranslated region of hepatitis C virus required for RNA replication. J Virol 2001; 75: 12047-12057.
- 27, , . Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J Virol 2001; 75: 4614-4624.
- 28, , , , . Cell culture adaptation of hepatitis C virus and in vivo viability of an adapted variant. J Virol 2007; 81: 13168-13179.
- 29, . Development and characterization of a transient-replication assay for the genotype 2a hepatitis C virus subgenomic replicon. J Gen Virol 2005; 86: 3075-3080.
- 30, , , , , , et al. Identification of determinants involved in initiation of hepatitis C virus RNA synthesis by using intergenotypic replicase chimeras. J Virol 2007; 81: 5270-5283.
- 31, , . Hepatitis C virus infection and apoptosis. World J Gastroenterol 2007; 13: 4865-4872.
- 32
- 33, , , . Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 2002; 123: 845-861.
- 34, , , , , , et al. Cytokine-induced hepatic apoptosis is dependent on FGL2/fibroleukin: the role of Sp1/Sp3 and STAT1/PU.1 composite cis elements. J Immunol 2006; 176: 7028-7038.
- 35, , , , , , et al. Reduced expression of Jak-1 and Tyk-2 proteins leads to interferon resistance in hepatitis C virus replicon. Virol J 2007; 4: 89.
- 36, , , , , , et al. 1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2. J Biol Chem 2003; 278: 30711-30718.
- 37, , , , , , et al. Identification of host genes involved in hepatitis C virus replication by small interfering RNA technology. HEPATOLOGY 2007; 45: 1413-1421.
- 38, , , , , , et al. Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. HEPATOLOGY 2007; 46: 1498-1508.
- 39. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest 2009; 119: 1745-1754.
- 40
- 41
- 42. Functional roles for T cell CD40 in infection and autoimmune disease: the role of CD40 in lymphocyte homeostasis. Semin Immunol 2009; 21: 283-288.
- 43. Regulatory roles and molecular signaling of TNF family members in osteoclasts. Gene 2005; 350: 1-13.

1527-3350/asset/olbannerleft.gif?v=1&s=4b2409f9534ed500d3c8da1940a23842e2b9932d)
1527-3350/asset/olbannerright.gif?v=1&s=141b9a8485298533c3e2016e937b0404f7d933e1)
