Mammalian target of rapamycin (mTOR) regulates TLR3 induced cytokines in human oral keratinocytes.
Mammalian target of rapamycin (mTOR) regulates TLR3 induced cytokines in human oral keratinocytes.
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DOI：
10.1016/j.molimm.2010.07.014
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发表时间：
2010-11
影响因子：
3.6
通讯作者：
Kinane DF
中科院分区：
文献类型：
--
作者：
Zhao J;Benakanakere MR;Hosur KB;Galicia JC;Martin M;Kinane DF
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-kB) in human oral keratinocytes. Taken together, these data demonstrate p70S6K, p4EBP1, JNK, NF-kB 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.
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影响因子：
4.2
作者：
Guggenheim, Bernhard;Gmuer, Rudolf;Kinane, Denis F.
通讯作者：
Kinane, Denis F.
影响因子：
7.3
作者：
Guertin, David A.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
64.8
作者：
Colina, Rodney;Costa-Mattioli, Mauro;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum
影响因子：
3.7
作者：
Benakanakere MR;Zhao J;Galicia JC;Martin M;Kinane DF
通讯作者：
Kinane DF
影响因子：
4.8
作者：
Du, KY;Montminy, M
通讯作者：
Montminy, M