Document Detail

Human BDCA3(+) dendritic cells are a potent producer of IFN-λ in response to hepatitis C virus.
MedLine Citation:
PMID:  23213063     Owner:  NLM     Status:  Publisher    
The polymorphisms in IL-28B (IFN-λ3) gene are strongly associated with the efficacy of HCV clearance. Dendritic cells (DCs) sense HCV and produce IFNs, thereby playing some cooperative roles with HCV-infected hepatocytes in the induction of interferon-stimulated genes (ISGs). BDCA3(+) DCs are discovered as a producer of IFN-λ upon toll-like receptor3(TLR3) agonist. We thus aimed to clarify the roles of BDCA3(+) DCs inanti-HCV innate immunity.Seventy healthy subjects and 20 patients with liver tumors were enrolled. BDCA3(+) DCs, in comparison with plasmacytoid DCs and myeloid DCs, were stimulated with TLR agonists, cell-cultured HCV (HCVcc) or Huh7.5.1 cells transfected with HCV/JFH-1. BDCA3(+) DCs were treated with anti-CD81 antibody, inhibitors for endosome acidification, TRIF-specific inhibitor or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-λ1, IL-28A/IFN-λ2 and IL-28B were quantified by subtype-specific ELISA. The frequency of BDCA3(+) DCs in PBMC was extremely low but higher in the liver. BDCA3(+) DCs recovered from PBMC or the liver released large amounts of IFN-λs, when stimulated with HCVcc or HCV-transfected Huh7.5.1.BDCA3(+) DCs were able to induce ISGs in the co-existing JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3(+) DCs with anti-CD81 antibody, cloroquine or bafilomycinA1 reduced HCVcc-induced IL-28B release, whereas BDCA3(+) DCs comparably produced IL-28B upon replication-defective HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3(+) DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3(+) DCs in healthy subjects with IL-28B major (rs8099917, TT) released more IL-28B than those with IL-28B minor genotype (TG). Conclusion: Human BDCA3(+) DCs,having tendency of being accumulated in the liver, recognize HCV by a CD81-, endosome- and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-λ3,the ability of which is superior in subjects with IL-28B major genotype. (HEPATOLOGY 2012.).
Sachiyo Yoshio; Tatsuya Kanto; Shoko Kuroda; Tokuhiro Matsubara; Koyo Higashitani; Naruyasu Kakita; Hisashi Ishida; Naoki Hiramatsu; Hiroaki Nagano; Masaya Sugiyama; Kazumoto Murata; Takasuke Fukuhara; Yoshiharu Matsuura; Norio Hayashi; Masashi Mizokami; Tetsuo Takehara
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-5
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 American Association for the Study of Liver Diseases.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
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