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-Preactivated Dendritic Cells1
* Department of Infectious, Parasitic, and Immuno-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy;
Neurology and Center for Experimental Neurological Therapy, S. Andrea Hospital, "La Sapienza" University of Rome, Rome, Italy; and
3M Pharmaceuticals, St. Paul, MN 55144
TLRs interact with a growing list of pathogen-derived products and these interactions drive the activation of innate and adaptive immune responses. Dendritic cells (DC) play a key role in these events expressing a heterogeneous repertoire of TLRs. We have previously demonstrated the production of type I IFNs in DC following bacterial infections and TLR triggering. In this study, we sought to characterize the transcriptome specifically induced in human DC by IFN-
production stimulated upon LPS treatment. To this aim, by using cDNA microarrays, we compared the transcriptome of DC following LPS treatment in the absence or presence of neutralizing anti-type I IFN Abs. Interestingly, we found that the expression of TLR7 was induced during LPS-induced maturation of DC in a type I IFN-dependent manner. The induction of TLR7 in maturing DC was mainly a consequence of the transcriptional activity of IRF-1, whose binding site was located within TLR7 promoter. Moreover, we also demonstrated that "priming" of immature DC, that usually express TLR8 but not TLR7, with exogenous IFN- induced a functionally active TLR7. In fact, treatment with the TLR7-specific ligand 3M-001 up-regulated the expression of CD83, CD86, and CD38 in IFN--primed DC but not in immature DC. Therefore, a robust enhancement in proinflammatory as well as regulatory cytokines was observed. These data suggest that TLR4-mediated type I IFN release activates specific transcription programs in DC amplifying the expression of pathogen sensors to correctly and combinatorially respond to a bacterial as well as viral infection.
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 grants from the Istituto Superiore di Sanità-National Institutes of Health Program (No. 5303), from Istituto Superiore di Sanita (No. 5AD/F2) and from Fondazione Italiana Sclerosi Multipla (Cod. 2005/R/7) to E.M.C.
2 Address correspondence and reprint requests to Dr. Eliana M. Coccia, Department of Infectious, Parasitic, and Immuno-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299-00161 Rome, Italy. E-mail address: e.coccia{at}iss.it
3 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; PRR, pattern recognition receptor; pDC, plasmacytoid DC; mDC, myeloid DC; TIR, Toll-IL-1R; TRIF, TIR-domain containing adapter inducing IFN-; IKK, I
B kinase; IRF, IFN regulatory factor; MFI, median fluorescent intensity; ISGF3, IFN-stimulated gene factor 3; ISG, IFN-stimulated gene; aRNA, antisense RNA; SOCS, suppressor of cytokine signaling; OAS, 2'-5'-oligoadenylate synthetase; CBA, cytometric bead array; TFBS, transcription factor binding site; TSS, transcription starting site; DEFB1, defensin-1; NOD, nucleotide-binding oligomerization domain; MDP, muramyl dipeptide.
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