期刊
MOLECULAR IMMUNOLOGY
卷 48, 期 1-3, 页码 294-304出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2010.07.014
关键词
Human oral keratinocytes; TLR3; mTOR; JNK; NF kappa B; IRF3
资金
- United States Public Health Service National Institutes of Health NIDCR [DE017384]
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 beta) tumor necrosis factor alpha (TNF alpha) IL-12p70 and interferon beta (IFN-beta) 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 56 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 beta TNF alpha IL-12p70 and IFN-beta was blocked by JNK inhibitor SP600125 TLR3 preferentially phosphorylated IKK alpha through mTOR to activate nuclear factor kappa beta (NF-kappa B) in human oral keratinocytes Taken together these data demonstrate p70S6K p4EBP1 JNK NF-kappa 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 (C) 2010 Elsevier Ltd All rights reserved
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