| First Author | Yin H | Year | 2016 |
| Journal | Biochim Biophys Acta | Volume | 1860 |
| Issue | 3 | Pages | 588-98 |
| PubMed ID | 26708990 | Mgi Jnum | J:251430 |
| Mgi Id | MGI:6104621 | Doi | 10.1016/j.bbagen.2015.12.012 |
| Citation | Yin H, et al. (2016) Syk negatively regulates TLR4-mediated IFNbeta and IL-10 production and promotes inflammatory responses in dendritic cells. Biochim Biophys Acta 1860(3):588-98 |
| abstractText | 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 IFNbeta and IL-10 but suppression of pro-inflammatory cytokines (TNFalpha, 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, GSK3beta. Inhibition of PI3K or Akt abrogated the ability of Syk deficiency to enhance IFNbeta and IL-10 in Syk deficient cells, confirmed by the overexpression of Akt (Myr-Akt) or constitutively active GSK3beta (GSK3 S9A). Moreover, neither inhibition of PI3K-Akt signaling nor neutralization of de novo synthesized IFNbeta could rescue TNFalpha and IL-6 production in LPS-stimulated Syk deficient cells. Syk deficiency resulted in decreased phosphorylation of IKKbeta and the NF-kappaB p65 subunit, further suggesting a divergent influence of Syk on pro- and anti-inflammatory TLR responses. CONCLUSIONS: Syk negatively regulates TLR4-mediated production of IFNbeta and IL-10 and promotes inflammatory responses in dendritic cells through divergent regulation of downstream PI3K-Akt and NF-kappaB signaling pathways. GENERAL SIGNIFICANCE: Syk may represent a novel target for manipulating the direction or intensity of the innate response, depending on clinical necessity. |
