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Sphingosine-1-phosphate can promote mast cell hyper-reactivity through regulation of contactin-4 expression.

ABSTRACT: Both genes and the environment are determinants in the susceptibility to allergies and may alter the severity of the disease. We explored whether an increase in the levels of the lipid mediator S1P in vivo, a condition found during allergic asthma, could affect the sensitivity or the response of MCs to IgE/Ag and the onset of allergic disease. We found that increasing S1P levels by genetic deletion of S1P lyase, the enzyme catabolizing S1P, led to elevated activity of circulating tryptase. Accordingly, MCs of S1P lyase-deficient mice were mostly degranulated in the tissues and showed enhanced calcium levels, degranulation, and cytokine production in response to IgE/Ag in vitro. Th 1-skewed mice (C57BL/6) had lower levels of S1P in circulation and histamine responses than did Th 2-skewed (129/Sv) mice. However, when S1P levels were increased by pharmacologic inhibition of S1P lyase, the C57BL/6 mice showed increased histamine release into the circulation and anaphylactic responses similar to those in the 129/Sv mice. Culturing of MCs in the presence of S1P enhanced their degranulation responses, and when the S1P-treated MCs were used to reconstitute MC-deficient (Kit(W-sh)) mice, they caused enhanced anaphylaxis. Gene expression arrays in S1P lyase-deficient MCs and MCs treated with S1P continuously revealed increased expression of numerous genes, including the adhesion molecule CNTN4,which contributed to the enhanced responses. Our findings argue that dysregulation in the metabolism of S1P is a contributing factor in modulating MC responsiveness and the allergic response.

SUBMITTER: Olivera A

PROVIDER: S-EPMC3800067 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Sphingosine-1-phosphate can promote mast cell hyper-reactivity through regulation of contactin-4 expression.

Olivera Ana A Kitamura Yoshiaki Y Wright Laurel D LD Allende Maria L ML Chen Weiping W Kaneko-Goto Tomomi T Yoshihara Yoshihiro Y Proia Richard L RL Rivera Juan J

Journal of leukocyte biology 20130731 5

Both genes and the environment are determinants in the susceptibility to allergies and may alter the severity of the disease. We explored whether an increase in the levels of the lipid mediator S1P in vivo, a condition found during allergic asthma, could affect the sensitivity or the response of MCs to IgE/Ag and the onset of allergic disease. We found that increasing S1P levels by genetic deletion of S1P lyase, the enzyme catabolizing S1P, led to elevated activity of circulating tryptase. Accor ...[more]

PMID: 23904439

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Project description:Sphingosine-1-phosphate (SPP) is a bioactive lipid that has recently been identified as the ligand for the EDG family of G protein-coupled cell surface receptors. However, the mitogenic and survival effects of exogenous SPP may not correlate with binding to cell-surface receptors (Van Brocklyn, J.R., M.J. Lee, R. Menzeleev, A. Olivera, L. Edsall, O. Cuvillier, D.M. Thomas, P.J.P. Coopman, S. Thangada, T. Hla, and S. Spiegel. 1998. J. Cell Biol. 142:229-240). The recent cloning of sphingosine kinase, a unique lipid kinase responsible for the formation of SPP, has provided a new tool to investigate the role of intracellular SPP. Expression of sphingosine kinase markedly increased SPP levels in NIH 3T3 fibroblasts and HEK293 cells, but no detectable secretion of SPP into the medium was observed. The increased sphingosine kinase activity in NIH 3T3 fibroblasts was sufficient to promote growth in low- serum media, expedite the G(1)/S transition, and increase DNA synthesis and the proportion of cells in the S phase of the cell cycle with a concomitant increase in cell numbers. Transient or stable overexpression of sphingosine kinase in NIH 3T3 fibroblasts or HEK293 cells protected against apoptosis induced by serum deprivation or ceramide elevation. N,N-Dimethylsphingosine, a competitive inhibitor of sphingosine kinase, blocked the effects of sphingosine kinase overexpression on cell proliferation and suppression of apoptosis. In contrast, pertussis toxin did not abrogate these biological responses. In Jurkat T cells, overexpression of sphingosine kinase also suppressed serum deprivation- and ceramide-induced apoptosis and, to a lesser extent, Fas-induced apoptosis, which correlated with inhibition of DEVDase activity, as well as inhibition of the executionary caspase-3. Taken together with ample evidence showing that growth and survival factors activate sphingosine kinase, our results indicate that SPP functions as a second messenger important for growth and survival of cells. Hence, SPP belongs to a novel class of lipid mediators that can function inside and outside cells.

Project description:BackgroundSphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR1-5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR1. This raises the question as to which other S1PRs mediate the enhanced excitability.MethodsIsolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR1/R2/R3 to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs).ResultsAfter siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR1 and R3 also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR1 and S1PR3, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR1 and R3 antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR1/R3/R4/R5), neither SEW2871 (S1PR1 selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR1), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons.ConclusionsThese results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR1 and/or S1PR3.

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Sphingosine-1-phosphate can promote mast cell hyper-reactivity through regulation of contactin-4 expression.

Publications

Sphingosine-1-phosphate can promote mast cell hyper-reactivity through regulation of contactin-4 expression.

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