title: Mammalian target of rapamycin (mTOR) regulates TLR3 induced cytokines in human oral keratinocytes.
abstract: Recent studies implicate the mammalian target of rapamycin (mTOR) pathway in the control of inflammatory responses following Toll-like receptor (TLR) stimulation in myeloid cells but its role in non-myeloid cells such as human keratinocytes is unknown. Here we show that TLR3 signaling can induce robust cytokine secretion including interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNFα), IL-12p70 and interferon beta (IFN-β), and our data reveal for the first time that inhibiting mTOR with rapamycin, suppresses these TLR3 induced responses but actually enhances bioactive IL-12p70 production in human oral keratinocytes. Rapamycin inhibited the phosphorylation of the 70-kDa ribosomal protein S6 kinase (p70S6K) and the 4E binding protein 1 (4EBP-1), and suppressed the mitogen activated protein kinase (MAPK) pathway by decreasing phosphorylation of c-Jun N-terminal kinase (JNK). We also show that TLR3 induces interferon regulatory factor 3 (IRF3) activation by Akt via an mTOR-p70S6K-4EBP1 pathway. Furthermore, we provide evidence that Poly I:C induced expression of IL-1β, TNFα, IL-12p70 and IFN-β was blocked by JNK inhibitor SP600125. TLR3 preferentially phosphorylated IKKα through mTOR to activate nuclear factor kappa beta (NF-κB) in human oral keratinocytes. Taken together, these data demonstrate p70S6K, p4EBP1, JNK, NF-κB and IRF3 are involved in the regulation of inflammatory mediators by TLR3 via the mTOR pathway. mTOR is a novel pathway modulating TLR3 induced inflammatory and antiviral responses in human oral keratinocytes.
authors: Department of Pathology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104, USA.
authors: Jiawei
authors: J
authors: Zhao
authors: Manjunatha R
authors: MR
authors: Benakanakere
authors: Kavita B
authors: KB
authors: Hosur
authors: Johnah C
authors: JC
authors: Galicia
authors: Michael
authors: M
authors: Martin
authors: Denis F
authors: DF
authors: Kinane
mesh_terms: D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009061:Mouth Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D050838:Interferon Regulatory Factor-3; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D011070:Poly I-C; D020123:Sirolimus