IFN-α Regulates TLR-Dependent Gene Expression of IFN-α, IFN-β, IL-28, and IL-29

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Abstract
Toll-like receptors (TLRs) mediate host cell activation by various microbial components. TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 are the receptors that have been associated with virus-induced immune response. We have previously reported that all these TLRs, except TLR9, are expressed at mRNA levels in human monocyte-derived macrophages. Here we have studied TLR2, TLR3, TLR4, and TLR7/8 ligand-induced IFN-α, IFN-β, IL-28, and IL-29 expression in human macrophages. IFN-α pretreatment of macrophages was required for efficient TLR3 and TLR4 agonist-induced activation of IFN-α, IFN-β, IL-28, and IL-29 genes. TLR7/8 agonist weakly activated IFN-α, IFN-β, IL-28, and IL-29 genes, whereas TLR2 agonist was not able to activate these genes. IFN-α enhanced TLR responsiveness in macrophages by up-regulating the expression of TLR3, TLR4, and TLR7. IFN-α also enhanced the expression of TLR signaling molecules MyD88, TIR domain-containing adaptor inducing IFN-β, IκB kinase-ε, receptor interacting protein 1, and IFN regulatory factor 7. Furthermore, the activation of transcription factor IFN regulatory factor 3 by TLR3 and TLR4 agonists was dependent on IFN-α pretreatment. In conclusion, our results suggest that IFN-α sensitizes cells to microbial recognition by up-regulating the expression of several TLRs as well as adapter molecules and kinases involved in TLR signaling.