ARTÍCULO

Dysregulation of interferon regulatory factors impairs the expression of immunostimulatory molecules in hepatitis C virus genotype 1-infected hepatocytes

Autores: Larrea Leoz, María Esther (Autor de correspondencia); Riezu Boj, José Ignacio; Aldabe Arregui, Rafael; Guembe Echarri, Laura; Echeverria Beistegui, Itziar; Balasiddaiah, A.; Gastaminza, P.; Civeira Murillo, María Pilar; Sarobe Ugarriza, Pablo; Prieto Valtueña, Jesús María (Autor de correspondencia)
Título de la revista: GUT
ISSN: 0017-5749
Volumen: 63
Número: 4
Páginas: 665 - 673
Fecha de publicación: 2014
Resumen:
Background IL-7 and IL-15 are produced by hepatocytes and are critical for the expansion and function of CD8 T cells. IL-15 needs to be presented by IL-15R¿ for efficient stimulation of CD8 T cells. Methods We analysed the hepatic levels of IL-7, IL-15, IL-15R¿ and interferon regulatory factors (IRF) in patients with chronic hepatitis C (CHC) (78% genotype 1) and the role of IRF1 and IRF2 on IL-7 and IL-15R¿ expression in Huh7 cells with or without hepatitis C virus (HCV) replicon. Results Hepatic expression of both IL-7 and IL-15R¿, but not of IL-15, was reduced in CHC. These patients exhibited decreased hepatic IRF2 messenger RNA levels and diminished IRF2 staining in hepatocyte nuclei. We found that IRF2 controls basal expression of both IL-7 and IL-15R¿ in Huh7 cells. IRF2, but not IRF1, is downregulated in cells with HCV genotype 1b replicon and this was accompanied by decreased expression of IL-7 and IL-15R¿, a defect reversed by overexpressing IRF2. Treating Huh7 cells with IFN¿ plus oncostatin M increased IL-7 and IL-15R¿ mRNA more intensely than either cytokine alone. This effect was mediated by strong upregulation of IRF1 triggered by the combined treatment. Induction of IRF1, IL-7 and IL-15R¿ by IFN¿ plus oncostatin M was dampened in replicon cells but the combination was more effective than either cytokine alone. Conclusions HCV genotype 1 infection downregulates IRF2 in hepatocytes attenuating hepatocellular expression of IL-7 and IL-15R¿. Our data reveal a new mechanism by which HCV abrogates specific T-cell responses and point to a novel therapeutic approach to stimulate anti-HCV immunity.