Sphingosine-1-Phosphate Contributes to TLR9-Induced TNF-α Release in  Lung Tumor Cells

Terlizzi, Michela; Colarusso, Chiara; Ferraro, Giusy; Monti, Maria Chiara; Cerqua, Ida; Roviezzo, Fiorentina; Pinto, Aldo; Sorrentino, Rosalinda

doi:10.33594/000000361

Cited by 10 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1P treatment induced a significant increase of TNF-α and IL-6 release from LK-derived PBMCs, but not from H-derived PBMCs ( Figure 1 A,B). These data further support what has already been observed, that S1P promotes pro-inflammatory patterns in lung cancer but not in physiological conditions [ 4 ]. However, it has to be noted that not all PBMCs responded to S1P treatment in terms of TNF-α and IL-6 release: 85.2% (46 out of 54) of lung cancer patients responded to S1P treatment with the release of TNF-α ( Figure 1 C, red slice), while 86.8% (46 out of 53) with IL-6 release ( Figure 1 D, red slice).…”

Section: Resultssupporting

confidence: 92%

“…In our previous studies, we found that lung cancer epithelial cells were responsive to exogenous S1P, but the major source of TNF-α was related to the activation of TLR9. In particular, TLR9 activation in lung cancer epithelial cells increased the release of TNF-α, but not of IL-6, through an imbalance of the ceramide/S1P rheostat in favor of S1P [ 4 ]. The activation of TLR9 led to the production of endogenous S1P, which, through an inside-out mode, favored TLR9/NF-κB-mediated TNF-α release via S1PR3 [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, TLR9 activation in lung cancer epithelial cells increased the release of TNF-α, but not of IL-6, through an imbalance of the ceramide/S1P rheostat in favor of S1P [ 4 ]. The activation of TLR9 led to the production of endogenous S1P, which, through an inside-out mode, favored TLR9/NF-κB-mediated TNF-α release via S1PR3 [ 4 ]. Here, instead, we found that S1P activity was related to S1PR3 on circulating cells of lung cancer patients but not by TLR9 (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…In another set of experiments, PBMCs were also treated with ceramidase inhibitor (D-NMAPPD, 5 µM; #SML2358; Sigma-Aldrich, Merck Life Science S.r.l., Milan, Italy), TY52156, a S1PR3 antagonist (αS1PR3, #5328; 10 µM; Tocris Bioscience, Ellisville, MO, USA), SKI II, a selective inhibitor of sphingosine kinases (SKI II, 10 µM; #2097; Tocris Bioscience, Ellisville, MO, USA), PF-543, a sphingosine-competitive inhibitor of sphingosine kinase I, SPHK I (PF543, 2 µM; #57177; Selleck Chemical, Houston, TX, USA), ABC294640 (Opaganib), a selective inhibitor of sphingosine kinase II, SPHK II (Opa, 60 µM; #915385-81-8; RedHill Biopharma, Tel-Aviv, Israel), FTI-276, a K-Ras inhibitor (FTI, 2 µg/mL; #F9553; Sigma-Aldrich, Merck Life Science S.r.l., Milan, Italy), Rapamycin, a potent and specific mTOR inhibitor (Rap, 100 ng/mL; #553210; Calbiochem, Sigma-Aldrich, Merck Life Science S.r.l., Milan, Italy), MG132, a proteasome inhibitor (MG132, 10 µM; #M8699; Sigma-Aldrich, Merck Life Science S.r.l., Milan, Italy). The concentration of all substances was chosen on the basis of the existing literature and on our previous experiments/data [ 4 , 5 ].…”

Section: Methodsmentioning

confidence: 99%

“…In our recent study, we demonstrated that the activation of Toll-like receptor 9 (TLR9) induced the synthesis of endogenous S1P in lung adenocarcinoma cells [ 4 ]. The endogenous S1P induced by TLR9 boosted the release of pro-inflammatory cytokines that, in the context of the lung tumor microenvironment, foster tumor proliferation.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

Terlizzi

Colarusso

Somma

et al. 2022

Cells

View full text Add to dashboard Cite

Sphingosine-1-phosphate (S1P) is involved in inflammatory signaling/s associated with the development of respiratory disorders, including cancer. However, the underlying mechanism/s are still elusive. The aim of this study was to investigate the role of S1P on circulating blood cells obtained from healthy volunteers and non-small cell lung cancer (NSCLC) patients. To pursue our goal, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with S1P. We found that the administration of S1P did not induce healthy PBMCs to release pro-inflammatory cytokines. In sharp contrast, S1P significantly increased the levels of TNF-α and IL-6 from lung cancer-derived PBMCs. This effect was S1P receptor 3 (S1PR3)-dependent. The pharmacological blockade of ceramidase and sphingosine kinases (SPHKs), key enzymes for S1P synthesis, completely reduced the release of both TNF-α and IL-6 after S1P addition on lung cancer-derived PBMCs. Interestingly, S1P-induced IL-6, but not TNF-α, release from lung cancer-derived PBMCs was mTOR- and K-Ras-dependent, while NF-κB was not involved. These data identify S1P as a bioactive lipid mediator in a chronic inflammation-driven diseases such as NSCLC. In particular, the higher presence of S1P could orchestrate the cytokine milieu in NSCLC, highlighting S1P as a pro-tumor driver.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

Terlizzi

Colarusso

Somma

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

Sphingosine 1-phosphate signaling during infection and immunity

Mohammed,

Bindu,

Viswanathan

et al. 2023

Progress in Lipid Research

View full text Add to dashboard Cite

Erythrocyte TLR9 is upregulated in metabolic associated fatty liver disease, and is linked to an inflammatory immunometabolic signature

Papadopoulos,

Mimidis,

Tentes

et al. 2024

Preprint

View full text Add to dashboard Cite

Metabolic associated fatty liver disease (MAFLD) consists of lipid accumulation in the liver. Lipotoxicity, supported by aberrant amino acid metabolism, induces TLR9 upregulation, and activation, driving inflammation. Relatively, erythrocyte TLR9 activation leads to membrane rearrangement, surface CD47 loss, and pro-inflammatory erythrophagocytosis. Erythrocyte surface protein loss is accompanied by chemokine release. In addition, CD47 binds circulating TSP-1, a molecule controlling arginine and glutamine metabolism, along with metabolic inflammation. Based on these, we speculated that in MAFLD, lipotoxicity would drive erythrocyte TLR9 upregulation and activation, leading to immunometabolic remodeling. Twenty-four patients (15 men and 9 women) with MAFLD and 9 healthy controls (4 men and 5 women) were enrolled. Erythrocytes were isolated from EDTA-containing blood. Protein levels were measured in erythrocyte lysates (triton X-100 0.01% v/v) or plasma with enzyme-linked immunosorbent assays, whereas lipids and enzyme activities were measured in erythrocyte hemoglobin-free membranes by a semi-quantitative thin layer chromatography and assay kits, respectively. The levels of TLR9 were increased (p=0.002) and positively correlated with sphingosine levels, albeit not statistically significantly (p=0.060). The erythrocyte membrane PC/PE ratio was decreased (p=0.002) and inversely correlated to TLR9 levels. Erythrocyte TLR9 levels correlated inversely with CD47, and positively with MCP-1 release. TSP-1 was decreased in MAFLD erythrocytes (p=0.0017) and correlated positively with CD47 and negatively with TLR9 levels. In vitro, erythrocytes of MAFLD patients bound less TSP-1 molecules. Erythrocytes of MAFLD patients also exhibit decreased arginase-1 protein (p=0.009) and activity (p=0.042). Glutaminase activity was increased, albeit to not statistically significantly different levels (p=0.25). The levels of CD35 were not different (p=0.65), excluding the role of erythrocyte aging for explaining these events. In MAFLD patients, erythrocyte TLR9 is upregulated and is associated with erythrocyte sphingolipid and glycerophospholipid perturbation, CD47 loss, MCP1 release, reduced TSP-1 scavenging, decreased arginase and increased glutaminase.

show abstract

Sphingosine-1-Phosphate Contributes to TLR9-Induced TNF-α Release in Lung Tumor Cells

Cited by 10 publications

References 0 publications

S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

Sphingosine 1-phosphate signaling during infection and immunity

Erythrocyte TLR9 is upregulated in metabolic associated fatty liver disease, and is linked to an inflammatory immunometabolic signature

Contact Info

Product

Resources

About