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

Eskan, Mehmet A.; Rose, Beate G.; Benakanakere, Manjunatha R.; Zeng, Qun; Fujioka, Daisuke; Martin, Michael; Lee, Menq Jer; Kinane, Denis F.

doi:10.1002/eji.200737898

Cited by 66 publications

(58 citation statements)

References 38 publications

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“…Our results are in accordance with the cooperation of TLR4 and S1P receptors to enhance inflammatory cytokine production in human gingival epithelial cells (33). In contrast, in a previous study we have observed that TLR2 and S1P 1/2 receptors interaction resulted in the inhibition of chemokine production in human monocytes/ macrophages (20).…”

Section: Discussionsupporting

confidence: 92%

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Fernández‐Pisonero

Dueñas

Barreiro

et al. 2012

The Journal of Immunology

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Given that TLRs and sphingosine-1-phosphate (S1P) are key players in inflammation, we explored the potential interplay between TLRs and S1P in the adhesion/inflammatory pathways in primary human endothelial cells. As determined by Western blot and flow cytometry, cells treated with LPS (a TLR4 ligand) and S1P showed significantly enhanced expression of adhesion molecules such as ICAM-1 and E-selectin compared with the effect of either ligand alone. Cell-type differences on E-selectin upregulation were observed. In contrast, no cooperation effect on ICAM-1 or E-selectin was observed with a TLR2/TLR1 ligand. Consistent with an increase in adhesion molecule expression, endothelial cell treatment with LPS plus S1P significantly enhanced adhesion of PBMCs under shear stress conditions compared with the effect of either ligand alone and exhibited comparable levels of cell adhesion strength as those after TNF-α treatment. Moreover, LPS and S1P cooperated to increase the expression of proinflammatory molecules such as IL-6, cyclooxygenase-2, and prostacyclin, as determined by ELISA and Western blot. The analysis of signaling pathways revealed the synergistic phosphorylation of ERK upon LPS plus S1P treatment of HUVEC and human aortic endothelial cells and cell-type differences on p38 and NF-κB activation. Moreover, pharmacological and small interfering RNA experiments disclosed the involvement of S1P1/3 and NF-κB in the cooperation effect and that cell origin determines the S1P receptors and signaling routes involved. Sphingosine kinase activity induction upon LPS plus S1P treatment suggests S1P– Sphingosine kinase axis involvement. In summary, LPS and S1P cooperate to increase proinflammatory molecules in endothelial cells and, in turn, to augment leukocyte adhesion, thus exacerbating S1P-mediated proadhesive/proinflammatory properties.

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Section: Discussionsupporting

confidence: 92%

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Fernández‐Pisonero

Dueñas

Barreiro

et al. 2012

The Journal of Immunology

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“…Since functional TLR4 has been observed in GEC (20), the observation of CD14 in these cells and its induction by vitamin D supports its role in amplification of the innate immune defense. Another surprising gene we observed to be expressed in these cells was the gene encoding PPBP (also known as CXCL7).…”

Section: Discussionmentioning

confidence: 82%

Vitamin D-Mediated Induction of Innate Immunity in Gingival Epithelial Cells

et al. 2011

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“…In KB cells (a HeLa-like carcinoma cell line), however, P. gingivalis Rgp appears to activate PAR-1 and PAR-2 and release IL-6, a potent stimulator of osteoclast differentiation and bone resorption (Lourbakos et al, 2001a). Hence, the PAR-gingipain specificity leading to release of pro-inflammatory cytokines is unclear, in part complicated by the presence of P. gingivalis LPS with concomitant activation through Tolllike receptors (TLRs) also leading to expression of proinflammatory cytokines (Chen et al, 2008;Diya et al, 2008;Eskan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains

et al. 2009

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Porphyromonas gingivalis activates protease-activated receptors (PARs) on oral keratinocytes, resulting in downstream signalling for an innate immune response. Activation depends on P. gingivalis gingipains, but could be confounded by lipopolysaccharide signalling through Toll-like receptors. We therefore hypothesized that P. gingivalis cleaves oral keratinocyte PARs in an Arg-(Rgp) or Lys-(Kgp) gingipain-specific manner to upregulate pro-inflammatory cytokines. Immortalized human oral keratinocytes (TERT-2) were incubated with wild-type P. gingivalis (ATCC 33277) or strains from a panel of isogenic gingipain deletion mutants: Kgp-deficient (KDP 129); Rgp-deficient (KDP 133); or Kgp-and Rgp-deficient (KDP 136). After incubation with P. gingivalis, keratinocytes were probed with specific antibodies against the N-terminus of PAR-1 and PAR-2. Using flow cytometry and immunofluorescence, receptor cleavage was marked by loss of specific antibody binding to the respective PARs. TERT-2 cells constitutively expressed high levels of PAR-1 and PAR-2, and lower levels of PAR-3. P. gingivalis ATCC 33277 cleaved PAR-1 and PAR-2 in a dose-dependent manner, while the receptors were unaffected by the protease-negative double mutant (KDP 136) at all m.o.i. tested. The single Kgp-negative mutant preferentially cleaved PAR-1, whereas the Rgp-negative mutant cleaved PAR-2. Wild-type or Kgp-negative mutant cleavage of PAR-1 upregulated expression of IL-1a, IL-1b, IL-6 and TNF-a; the Rgp-negative mutant did not modulate these cytokines. Selective cleavage of PAR-1 on oral epithelial cells by P. gingivalis Rgp therefore upregulates expression of pro-inflammatory cytokines.

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

Cited by 66 publications

References 38 publications

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Lipopolysaccharide and Sphingosine-1-Phosphate Cooperate To Induce Inflammatory Molecules and Leukocyte Adhesion in Endothelial Cells

Vitamin D-Mediated Induction of Innate Immunity in Gingival Epithelial Cells

Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains

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