PMID- 18758466 OWN - NLM STAT- MEDLINE DCOM- 20081014 LR - 20211203 IS - 1529-2916 (Electronic) IS - 1529-2908 (Print) IS - 1529-2908 (Linking) VI - 9 IP - 10 DP - 2008 Oct TI - Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. PG - 1157-64 LID - 10.1038/ni.1645 [doi] AB - Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs. FAU - Cao, Weiping AU - Cao W AD - Emory Vaccine Center, Atlanta, GA 30329, USA. FAU - Manicassamy, Santhakumar AU - Manicassamy S FAU - Tang, Hua AU - Tang H FAU - Kasturi, Sudhir Pai AU - Kasturi SP FAU - Pirani, Ali AU - Pirani A FAU - Murthy, Niren AU - Murthy N FAU - Pulendran, Bali AU - Pulendran B LA - eng GR - R37 AI048638/AI/NIAID NIH HHS/United States GR - R01 DK057665/DK/NIDDK NIH HHS/United States GR - AI0564499/AI/NIAID NIH HHS/United States GR - N01AI50019/AI/NIAID NIH HHS/United States GR - R37 DK057665/DK/NIDDK NIH HHS/United States GR - R01 AI048638/AI/NIAID NIH HHS/United States GR - DK057665/DK/NIDDK NIH HHS/United States GR - U54 AI057157/AI/NIAID NIH HHS/United States GR - AI048638/AI/NIAID NIH HHS/United States GR - U19 AI057266/AI/NIAID NIH HHS/United States GR - AI05726601/AI/NIAID NIH HHS/United States GR - AI057157/AI/NIAID NIH HHS/United States GR - R56 AI048638/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20080831 PL - United States TA - Nat Immunol JT - Nature immunology JID - 100941354 RN - 0 (Immunosuppressive Agents) RN - 0 (Interferon Type I) RN - 0 (Tlr9 protein, mouse) RN - 0 (Toll-Like Receptor 9) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Dendritic Cells/drug effects/immunology/*metabolism MH - Electrophoresis, Polyacrylamide Gel MH - Flow Cytometry MH - Gene Expression Regulation/immunology MH - Humans MH - Immunoblotting MH - Immunosuppressive Agents/pharmacology MH - Interferon Type I/immunology/*metabolism MH - Mice MH - Mice, Knockout MH - Oligonucleotide Array Sequence Analysis MH - Phosphatidylinositol 3-Kinases/immunology/metabolism MH - Protein Kinases/immunology/*metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/immunology/metabolism MH - Signal Transduction/*immunology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases MH - Toll-Like Receptor 9/immunology/*metabolism MH - Transfection PMC - PMC3732485 MID - NIHMS494939 EDAT- 2008/09/02 09:00 MHDA- 2008/10/15 09:00 PMCR- 2013/08/03 CRDT- 2008/09/02 09:00 PHST- 2008/06/26 00:00 [received] PHST- 2008/07/21 00:00 [accepted] PHST- 2008/09/02 09:00 [pubmed] PHST- 2008/10/15 09:00 [medline] PHST- 2008/09/02 09:00 [entrez] PHST- 2013/08/03 00:00 [pmc-release] AID - ni.1645 [pii] AID - 10.1038/ni.1645 [doi] PST - ppublish SO - Nat Immunol. 2008 Oct;9(10):1157-64. doi: 10.1038/ni.1645. Epub 2008 Aug 31.