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* Center for Oral Health and Systemic Disease, Department of Periodontics, Endodontics, and Dental Hygiene, University of Louisville School of Dentistry, Louisville, KY 40202; and
Gheens Center on Aging, Microbiology, and Immunology, University of Louisville School of Medicine, Louisville, KY 40292
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.
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1 This work was supported by National Institutes of Health grant DE017384.
2 Address correspondence and reprint requests to Dr. Denis F. Kinane, University of Louisville School of Dentistry, Oral Health and Systemic Disease, 501 South Preston Street, Room 204, Louisville, KY 40202. E-mail address: denis.kinane{at}louisville.edu
3 Abbreviations used in this paper: GPCR, G protein-coupled receptor; HGEC, human gingival epithelial cell; IRF3, IFN-regulatory factor 3; PTx, pertussis toxin; qPCR, quantitative PCR; RNAi, RNA interference; S1P, sphingosine 1-phosphate; si, small interfering; SEW, 5-(4-phenyl-5-trifluoromethylthiophen-2-yl)-3-(3-trifluoromethylphenyl)-(1,2,4)-oxadiazole.
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