Src family kinases and lipid mediators in control of allergic inflammation

Abstract

The Src family kinases Fyn and Lyn are important modulators of the molecular events initiated by engagement of the high-affinity IgE receptor (Fc epsilon RI). These kinases control many of the early signaling events and initiate the production of several lipid metabolites that have an important role in regulating mast cell responses. The intracellular level of phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), which is produced by phosphatidylinositol 3-OH kinase, plays an important role in determining the extent of a mast cells response to a stimulus. Enhanced levels lead to a hyperdegranulating phenotype (as seen in SHIP-1(-/-) and Lyn(-/-) mast cells), whereas decreased levels cause hypodegranulation (as seen in Fyn(-/-) mast cells). Downregulation of mast cell phosphatase and tensin homologue deleted on chromosone 10 expression, a phosphatase that reduces cellular levels of PIP(3), caused constitutive cytokine production, demonstrating that this response is particularly sensitive to PIP(3) levels. Lyn and Fyn are also intimately linked to other lipid kinases, like sphingosine kinases (SphK). By producing sphingosine-1-phosphate (S1P), SphKs contribute to mast cell chemotaxis and degranulation. In vivo studies now reveal that circulating S1P as well as that found within the mast cell is important in determining mast cell responsiveness. These studies demonstrate the connection between Src protein tyrosine kinases and lipid second messengers that control mast cell function and allergic responses.