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

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.