Sphingosine 1-Phosphate 1 and TLR4 Mediate IFN-β Expression in Human Gingival Epithelial Cells

Abstract

IFN-β production is a critical step in human innate immune responses and is primarily controlled at the transcription level by highly ordered mechanisms. IFN-β can be induced by pattern-recognition receptors such as the TLR4. S1P1 is a G protein-coupled receptor, which has a high affinity for sphingosine 1-phosphate (S1P). Although many of the receptors and signaling pathways leading to the expression of IFN-β have been identified and characterized, it is still unclear how IFN-β is regulated in primary human gingival epithelial cells (HGECs). In this study, we demonstrate that S1P1 and TLR4, acting in unison, play an important role in IFN-β expression at the protein and mRNA level in HGECs. We demonstrate that the expression of both IFN-β and IFN-inducible protein-10 (CXCL-10) is significantly up-regulated by LPS and S1P or LPS and a specific S1P1 agonist. This enhanced innate immune response is attenuated in HGECs by small interfering RNA knockdown of either TLR4 or S1P1. Moreover, we show that triggering of TLR4 results in the increased expression of S1P1 receptors. Furthermore, we found that IFN-regulatory factor 3 activation was maximized by LPS and S1P through PI3K. Our data show that triggering TLR4 increases S1P1, such that both TLR4 and S1P1 acting through PI3K enhancement of IFN-regulatory factor 3 activation increase IFN-β expression in epithelial cells. The functional association between TLR4 and the S1P1 receptor demonstrates a novel mechanism in the regulation of IFN-β and CXCL-10 in human primary gingival epithelial cells.

Scaffolding Adaptor Protein Gab1 Is Required for TLR3/4- and RIG-I–Mediated Production of Proinflammatory Cytokines and Type I IFN in Macrophages

“…TLR4 activates PI3K to maximize IRF3 activation and subsequently induce IFN-b and IP-10 in human epithelial cells (36). In our study, we found that Gab1 enhances TLR3-and TLR4-triggered activation of MAPKs, NF-kB, but also promotes MyD88-dependent, TRIF-dependent, or RIG-Itriggered IRF3 activation.…”

TLR2/1 and sphingosine 1-phosphate modulate inflammation, myofibroblast differentiation and cell migration in fibroblasts

“…In macrophages and T cells, S1P attenuates TLR2 signaling and TLRinduced IL-8 production, respectively [39,40]. In contrast, S1P and TLR4 cooperatively induce pro-inflammatory cytokine expression and type I IFNs in gingival epithelial and endothelial cells [28,29,41]. We show here that IL-6 and IL-8 production is increased by costimulation with S1P and Pam 3 CSK 4 or poly(I:C) (Fig.…”

Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response

“…Plots of GPLSs from the 32 genes in cluster 219, 220, and 243 showed very similar patterns, all having a major peak at one end of chromosome 13, a secondary peak on chromosome 10, and a third peak on chromosome 4 (Figure 3A–3E). Among the 32 genes in the three clusters, at least 16 (50%; Oas1g, Tgfb3, Tnfrsf12a, Stat2, Parp14, Oas1a, Adar1, Mx2, Irf7, S1pr5, Oas2, Dhx58, Ifit3, Usp18, Isg15, and Ifi35 ) were known to play a role (or induced by) in the IFN-I response (Chapman et al, 2013; Eskan et al, 2008; George et al, 2011). Search of an interferon database (Rusinova et al, 2013) identified an additional nine genes ( Hbegf, Cstb, Fcγr1, Tnc, Errfi1, Wisp1, Kazad1, Rtp4, and B430306N03Rik ) that have been implicated in the IFN-I response, increasing the percentage to 78.1% (25/32).…”