Hepatitis C virus core protein induces an anergic state characterized by decreased interleukin-2 production and perturbation of mitogen-activated protein kinase responses.
Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infections, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Here we demonstrate that the expression of the HCV core (C) protein in stably transfected T cells correlates with a selective reduction of interleukin-2 (IL-2) promoter activity and IL-2 production in response to T-cell receptor triggering, whereas the activation of IL-4, IL-10, gamma interferon, and tumor necrosis factor alpha was moderately increased. This altered cytokine expression profile was associated with a perturbation of mitogen-activated protein (MAP) kinase responses. Extracellular regulated kinase and p38 were constitutively phosphorylated in C-expressing cells, while triggering of the costimulatory c-Jun N-terminal kinase (JNK) signaling cascade and activation of the CD28 response element within the IL-2 promoter appeared to be impaired. The perturbations of MAP kinase phosphorylation could be eliminated by cyclosporine A-mediated inhibition of nuclear factor of activated T cells, suggesting that the inactivation of JNK signaling and hyporesponsiveness to IL-2 induction were downstream consequences of C-induced Ca(2+) flux in a manner that mimics the induction of clonal anergy.
Sundström
Sara
S
Microbiology and Tumor Biology Centre, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Ota
Seisuke
S
Dimberg
Lina Y
LY
Masucci
Maria G
MG
Bergqvist
Anders
A
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D017635:Clonal Anergy; D004789:Enzyme Activation; D016174:Hepacivirus; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D019169:Jurkat Cells; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000494:pharmacology*
D007376:Interleukin-2; D014758:Viral Core Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases