Expression of type III interferon (IFN) in the vaginal mucosa is mediated primarily by dendritic cells and displays stronger dependence on NF-kappaB than type I IFNs.
Interferons (IFNs) are induced as an initial response to viral infection after recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Here, we report that different PAMPs induce type I and III IFN expression at different ratios after mucosal administration in the vaginas of mice and that Toll-like receptor 9 (TLR9) stimulation evokes a particularly strong IFN-lambda response, which is essential for optimal antiviral protection. Depletion of CD11c(+) cells in vivo revealed that dendritic cells (DCs) in the vaginal epithelium are a key source of type I and III IFNs during herpes simplex virus infection and after specific stimulation of TLR9. A comparison of the signaling pathways activated by TLR9 and cytoplasmic PRRs, which induced lower levels of IFN-lambda, revealed that high-level induction of IFN-lambda correlated with strong activation of NF-kappaB p65. Inhibition of the NF-kappaB and interferon regulatory factor 3 (IRF-3) pathways with the NEMO-binding domain peptide and small interfering RNA (siRNA), respectively, revealed that transcription of the type III IFN genes was more dependent on the NF-kappaB pathway than that of the type I IFN genes, which relied more on the IRF system. Thus, the type I and III IFN genes are not induced through entirely identical pathways, which indicates differential expression of these two types of IFNs under certain conditions.
Iversen
Marie B
MB
Department of Medical Microbiology and Immunology, Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark.
Ank
Nina
N
Melchjorsen
Jesper
J
Paludan
Søren R
SR
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D007372:Interferons / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology*; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D018139:Simplexvirus / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014621:Vagina / Q000276:immunology*
D050838:Interferon Regulatory Factor-3; D052002:NF-kappa B p50 Subunit; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C073701:Nfkb1 protein, mouse; D007372:Interferons