Regulation of IFN regulatory factor-7 and IFN-alpha production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells.
Human plasmacytoid dendritic cells (PDC) are a major source of IFN-alpha upon exposure to enveloped viruses and TLR-7 and TLR-9 ligands. Although IFN regulatory factor-7 (IRF-7) is known to play an essential role in virus-activated transcription of IFN-alpha genes, the molecular mechanisms of IFN-alpha production in human PDC remain poorly understood. We and others have recently reported high constitutive levels of IRF-7 expression in PDC as compared with other PBMC. In this study, we demonstrate that both LPS and HSV up-regulate the expression of IRF-7 in PDC, and that this enhancement of IRF-7 is dependent on NF-kappa B activation. The NF-kappa B inhibitors MG132 and pyrrolidinedithiocarbamate efficiently inhibited the induction of IRF-7 by HSV or LPS, and also down-regulated the constitutive expression of IRF-7 in PDC and blocked the HSV-induced production of IFN-alpha. In addition, we found that nuclear translocation of IRF-7 occurred rapidly in response to HSV stimulation, but not in response to LPS, which is consistent with the stimulation of IFN-alpha production by virus and not by LPS. Although LPS by itself was not able to induce IFN-alpha production, it led to rapid up-regulation of TLR-4 on PDC and increased the magnitude and accelerated the kinetics of HSV-induced IFN-alpha production in PDC, providing a mechanism that might be operative in a scenario of mixed infection. In contrast to the current concept of IFN-alpha regulation established in cell lines, this study strongly supports the immediate availability of high constitutive levels of IRF-7 expression in PDC, and suggests an activation required for IRF-7 that contributes to IFN-alpha production in virus-stimulated PDC.
Dai
Jihong
J
University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.
Megjugorac
Nicholas J
NJ
Amrute
Sheela B
SB
Fitzgerald-Bocarsly
Patricia
P
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D004285:Dogs; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D009980:Influenza A virus / Q000502:physiology; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney; D007976:Leupeptins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011112:Polymyxin B / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D029082:Sendai virus / Q000502:physiology; D013859:Thiocarbamates / Q000494:pharmacology; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D007976:Leupeptins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D013859:Thiocarbamates; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C020972:pyrrolidine dithiocarbamic acid; D011112:Polymyxin B; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde