期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1860, 期 3, 页码 588-598出版社
ELSEVIER
DOI: 10.1016/j.bbagen.2015.12.012
关键词
Syk; Toll-like receptor 4; Interferon-beta; IL-10; PI3K; GSK3 beta
资金
- National Institute of Dental and Craniofacial Research, NIH [DE023633, DE017921, DE011111, DE025388, DE017680]
- Kentucky Science and Engineering Foundation [KSEF-148-502-15-349]
- Kentucky Science and Technology Corporation
Background: While Syk has been shown to associate with TLR4, the immune consequences of Syk-TLR interactions and related molecular mechanisms are unclear. Methods: Gain-and loss-of-function approaches were utilized to determine the regulatory function of Syk and elucidate the related molecular mechanisms in TLR4-mediated inflammatory responses. Cytokine production was measured by ELISA and phosphorylation of signaling molecules determined by Western blotting. Results: Syk deficiency in murine dendritic cells resulted in the enhancement of LPS-induced IFN beta, and IL-10 but suppression of pro-inflammatory cytokines (TNF alpha, IL-6). Deficiency of Syk enhanced the activity of PI3K and elevated the phosphorylation of PI3K and Akt, which in turn, lead to the phospho-inactivation of the downstream, central gatekeeper of the innate response, GSK3 beta. Inhibition of PI3K or Akt abrogated the ability of Syk deficiency to enhance IFN beta and IL-10 in Syk deficient cells, confirmed by the overexpression of Akt (Myr-Akt) or constitutively active GSK3 beta (GSIC3 S9A). Moreover, neither inhibition of PI3K-Akt signaling nor neutralization of de novo synthesized IFN beta could rescue TNF alpha and IL-6 production in LPS-stimulated Syk deficient cells. Syk deficiency resulted in decreased phosphorylation of IKK beta and the NF-kappa B p65 subunit, further suggesting a divergent influence of Syk on pro-and anti-inflammatory TLR responses. Conclusions: Syk negatively regulates TLR4-mediated production of IFN beta and IL-10 and promotes inflammatory responses in dendritic cells through divergent regulation of downstream PI3K-Akt and NF-kappa B signaling pathways. General significance: Syk may represent a novel target for manipulating the direction or intensity of the innate response, depending on clinical necessity. (C) 2015 Elsevier B.V. All rights reserved.
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