Differential involvement of IFN-beta in Toll-like receptor-stimulated dendritic cell activation.
Toll-like receptor (TLR) can activate dendritic cells (DC) through common signaling pathways requiring a cytoplasmic adapter, MyD88. However, the signaling is differentially regulated among TLR family members. TLR4 can activate MyD88-deficient bone marrow-derived DC (BMDC), and lead to induction of IFN-inducible genes and up-regulation of co-stimulatory molecules such as CD40, implying that the MyD88-independent signaling pathway functions downstream of TLR4. Because these effects can also be induced by type I IFN, we have analyzed whether type I IFN is involved in TLR4-induced responses. In response to lipopolysaccharide (LPS), IFN-beta gene expression was augmented in both wild-type and MyD88-deficient BMDC. Expression of all IFN-inducible genes except immune-responsive gene 1 (IRG1) was abolished and CD40 up-regulation was decreased in LPS-stimulated BMDC lacking either IFN-alpha/beta receptor (IFN-alpha/betaR) or signal transducer and activator of transcription 1 (STAT-1). Similar to the LPS response, TLR9 signaling can also induce expression of IFN-beta and IFN-inducible genes, and up-regulation of CD40. However, all these effects were MyD88 dependent. Thus, in TLR4 signaling, IFN-beta expression can be induced either by the MyD88-dependent or -independent pathway, whereas, in TLR9 signaling, it is dependent on MyD88. In CpG DNA-stimulated DC, expression of IFN-inducible genes except IRG1 was dependent on type I IFN signaling as in LPS-stimulated DC. However, in contrast to TLR4 signaling, TLR9 signaling requires type I IFN signaling for CD40 up-regulation. Taken together, this study demonstrates differential involvement of type I IFN in TLR4- and TLR9-induced effects on DC.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D019013:CD40 Antigens / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D029721:Drosophila Proteins; D016899:Interferon-beta / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000502:physiology*; D018121:Receptors, Cytokine / Q000235:genetics; D011971:Receptors, Immunologic / Q000502:physiology; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C104577:IP10-Mig receptor; C428425:Ifi27 protein, rat; C431543:Ifit1 protein, rat; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D016899:Interferon-beta