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Coron Artery Dis. 2014 Jun;25(4):311-20. doi: 10.1097/MCA.0000000000000082.

TNF-α production in NKT cell hybridoma is regulated by sphingosine-1-phosphate: implications for inflammation in atherosclerosis.

Author information

1
aDepartment of Molecular and Cellular Pathobiology and Therapeutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya bDivision of Immunology, Kitasato University School of Medicine, Sagamihara cDepartment of Clinical Laboratory, University of Tokyo Hospital, Tokyo dDepartment of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Abstract

OBJECTIVES:

Natural killer T (NKT) cells are unique T lymphocytes that recognize glycolipid antigen and produce various cytokines. NKT cells accelerate atherosclerosis in mice. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and regulates T-lymphocyte trafficking. We aimed to determine the effects of S1P on the production of proinflammatory cytokine, tumor necrosis factor (TNF)-α, in NKT cell hybridomas and mouse NKT cells.

MATERIALS AND METHODS:

NKT cell hybridomas and sorted mouse NKT cells were stimulated with S1P and α-galactosylceramide (α-GalCer), the major ligand to produce cytokines in NKT cells. TNF-α mRNA expression and protein production were determined by real-time PCR and ELISA, respectively. Cell migration was assayed using chemotaxicell. Plasma S1P was measured using HPLC.

RESULTS:

Hybridomas expressed S1P receptors, S1P1, S1P2, and S1P4. S1P and α-GalCer increased TNF-α mRNA expression and protein production. S1P enhanced TNF-α induction by α-GalCer. S1P receptor antagonists decreased the TNF-α mRNA expression induced by S1P. FTY720, an immunosuppressive S1P receptor modulator, also decreased the TNF-α mRNA expression. The migration of NKT cell hybridomas was increased by S1P. FTY720 reduced the migration induced by S1P. S1P also increased the TNF-α mRNA expression in mouse NKT cells. Plasma TNF-α levels in patients with high plasma S1P (≥500 nmol/l) were higher than those in patients with low S1P (<500 nmol/l).

CONCLUSION:

S1P binds to S1P receptors in NKT cells and enhances TNF-α production. TNF-α overproduction may induce atherogenic inflammatory responses. S1P may serve as a novel therapeutic target for amelioration of vascular inflammatory diseases.

PMID:
24448174
DOI:
10.1097/MCA.0000000000000082
[Indexed for MEDLINE]
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