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-1?), tumor necrosis factor alpha (TNF?), IL-12p70 and interferon beta (IFN-?), 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-1?, TNF?, IL-12p70 and IFN-? was blocked by JNK inhibitor SP600125. TLR3 preferentially phosphorylated IKK? through mTOR to activate nuclear factor kappa beta (NF-?B) in human oral keratinocytes. Taken together, these data demonstrate p70S6K, p4EBP1, JNK, NF-?B 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.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC4372152 | biostudies-literature | 2010 Nov-Dec

REPOSITORIES: biostudies-literature