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Dual Signaling of MyD88 and TRIF Is Critical for Maximal TLR4-Induced Dendritic Cell Maturation¹

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510

TLR4 is a unique TLR because downstream signaling occurs via two separate pathways, as follows: MyD88 and Toll IL-1 receptor (TIR) domain-containing adaptor-inducing IFN-β (TRIF). In this study, we compared and contrasted the interplay of these pathways between murine dendritic cells (DCs) and macrophages during LPS stimulation. During TLR4 activation, neither pathway on its own was critical for up-regulation of costimulatory molecules in DCs, whereas the up-regulation of costimulatory molecules was largely TRIF dependent in macrophages. LPS-induced secreted factors, of which type I IFNs were one of the active components, played a larger role in promoting the up-regulation of costimulatory molecules in macrophages than DCs. In both cell types, MyD88 and TRIF pathways together accounted for the inflammatory response to LPS activation. Furthermore, signaling of both adaptors allowed maximal T cell priming by LPS-matured DCs, with MyD88 playing a larger role than TRIF. In sum, in our experimental systems, TRIF signaling plays a more important role in LPS-induced macrophage activation than in DC activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI064660 and AG028082 (to D.R.G.). W.E.W. is supported by National Institutes of Health Grant 5T32HL007778.

² Address correspondence and reprint requests to Dr. Daniel R. Goldstein, Department of Internal Medicine, Yale University School of Medicine, 3FMP, 333 Cedar Street, New Haven, CT 06510. E-mail address: daniel.goldstein{at}yale.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; DKO, double deficient; IRF, IFN regulatory factor; MFI, mean fluorescence intensity; pDC, plasmacytoid DC; TGC-PECs, thioglycolate-elicited macrophages; TIR, Toll IL-1 receptor; TRIF, TIR domain-containing adaptor-inducing IFN-β; UCM, up-regulation of costimulatory molecules; WT, wild type.

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