TLR4 and S1P receptors cooperate to enhance inflammatory cytokine production in human gingival epithelial cells

Toll-like receptors (TLR) are pattern recognition receptors for highly conserved microbial molecular patterns. Activation of TLR is a pivotal step in the initiation of innate, inflammatory, and immune defense mechanisms. Recent findings indicate that G protein-coupled receptors (GPCR) may modulate T...

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Bibliographic Details
Published in:European journal of immunology 2008-04, Vol.38 (4), p.1138-1147
Main Authors: Eskan, Mehmet A, Rose, Beate G, Benakanakere, Manjunatha R, Zeng, Qun, Fujioka, Daisuke, Martin, Michael H, Lee, Menq-Jer, Kinane, Denis F
Format: Article
Language:English
Subjects:
Cells, Cultured
Cytokines
Cytokines - biosynthesis
Enzyme Activation - drug effects
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Gingiva - drug effects
Gingiva - metabolism
Humans
Lipopolysaccharides - pharmacology
Lysophospholipids - metabolism
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Receptors, Lysosphingolipid - metabolism
S1P1
S1P3
Signal Transduction - drug effects
Sphingosine - analogs & derivatives
Sphingosine - metabolism
TLR4
Toll-Like Receptor 4 - metabolism
Up-Regulation - drug effects
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Summary:Toll-like receptors (TLR) are pattern recognition receptors for highly conserved microbial molecular patterns. Activation of TLR is a pivotal step in the initiation of innate, inflammatory, and immune defense mechanisms. Recent findings indicate that G protein-coupled receptors (GPCR) may modulate TLR signaling, but it is unclear which GPCR are involved in this process. One such cooperation between GPCR and TLR can be attributed to the sphingosine 1-phosphate (S1P) receptor family. The S1P receptors (S1P₁₋₅) are a family of GPCR with a high affinity for S1P, a serum-borne bioactive lipid associated with diverse biological activities such as inflammation and healing. In this study, we show that pro-inflammatory cytokine production, including IL-6 and IL-8, was increased with LPS and concomitant S1P stimulation. Furthermore, elevated cytokine production following LPS and S1P challenge in human gingival epithelial cells (HGEC) was significantly reduced when TLR4, S1P₁ or S1P₃ signaling was blocked. Our study also shows that S1P₁ and S1P₃ expression was induced by LPS in HGEC, and this elevated expression enhanced the influence of S1P in its cooperation with TLR4 to increase cytokine production. This cooperation between TLR4 and S1P₁ or S1P₃ demonstrates that TLR4 and GPCR can interact to enhance cytokine production in epithelial cells.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200737898