International Immunology, Vol. 14, No. 10, pp. 1225-1231,
October 2002
© 2002 Japanese Society for Immunology
Differential involvement of IFN-ß in Toll-like receptor-stimulated dendritic cell activation
1 Department of Host Defense and Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan 2 SORST, Japan Science and Technology Corp., Suita, Osaka 565-0871, Japan 3 RIKEN Research Center for Allergy and Immunology, Yokahama, Kanagawa 230-0045, Japan 4 Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Tottori 683-8504, Japan
Correspondence to: S. Akira; E-mail: sakira{at}biken.osaka-u.ac.jp
Transmitting editor: T. Kurosaki
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-ß 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-
/ß receptor (IFN-/ßR) or signal transducer and activator of transcription 1 (STAT-1). Similar to the LPS response, TLR9 signaling can also induce expression of IFN-ß and IFN-inducible genes, and up-regulation of CD40. However, all these effects were MyD88 dependent. Thus, in TLR4 signaling, IFN-ß 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.
Keywords: CD40, dendritic cell, innate immunity, lipopolysaccharide, Toll-like receptor
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