title: Hepatitis B virus (HBV) induces the expression of interleukin-8 that in turn reduces HBV sensitivity to interferon-alpha.
abstract: High levels of serum interleukin-8 (IL-8) have been detected in chronic hepatitis B (CHB) patients during episodes of hepatitis flares. We investigated whether hepatitis B virus (HBV) may directly induce IL-8 production and whether IL-8 may antagonize interferon-alpha (IFN-α) antiviral activity against HBV. We showed that CHB patients had significantly higher IL-8 levels both in serum and in liver tissue than controls. In HBV-replicating HepG2 cells, IL-8 transcription was significantly activated. AP-1, C/EBP and NF-kB transcription factors were concurrently necessary for maximum IL-8 induction. Moreover, HBx viral protein was recruited onto the IL-8 promoter and this was paralleled by IL8-bound histone hyperacetylation and by active recruitment of transcriptional coactivators. Inhibition of IL-8 increases the antiviral activity of IFN-α against HBV. Our results indicate that HBV activates IL-8 gene expression by targeting the epigenetic regulation of the IL-8 promoter and that IL-8 may contribute to reduce HBV sensitivity to IFN-α.
authors.affiliation: Department of Pediatric, Gynecologic, Microbiological, and Biomedical Sciences, University of Messina, Messina, Italy. tpollicino@unime.it
authors.forename: Teresa
authors.initials: T
authors.lastname: Pollicino
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellinghieri
authors.forename: Agnese
authors.initials: A
authors.lastname: Restuccia
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Raffa
authors.forename: Cristina
authors.initials: C
authors.lastname: Musolino
authors.forename: Angela
authors.initials: A
authors.lastname: Alibrandi
authors.forename: Diana
authors.initials: D
authors.lastname: Teti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raimondo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D005260:Female; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology*; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: C508606:CXCL8 protein, human; D016898:Interferon-alpha; D016209:Interleukin-8
keywords: Chromatin immunoprecipitation; Chromatin modifying enzymes; Hepatitis B X viral regulatory protein; Hepatitis B virus chronic infection; IL-8 promoter; IL-8 siRNA; Interferon-alpha; Interleukin-8; Signal pathways; Transcription factors