Mast cells (MCs) initiate allergic responses and are involved in innate protection from infections. MC activation through the high-affinity Fc receptor for IgE (FcsRI) induces de novo synthesis of two major eicosanoids: cysteinyl leukotrienes (cysLTs), formed by the 5-lipoxygenase/leukotriene C4 synthase {5-LO/LTC4S) pathway, and prostaglandin (PG) D2, a product of the PGH synthase (PGHS)/PGD synthase pathway sequence. Both cysLTs and PGD2 act through specific receptor systems to mediate MC-dependent bronchconstriction, leukocyte recruitment, and airway hyperresponsiveness in vivo. Another eicosanoid, PGE2l is markedly bronchoprotective in both allergic and aspirin-intolerant asthma (AIA). Preliminary data now reveal that cord blood-derived human MCs (hMCs) respond to stimulation with staphylococcal peptidoglyan (PGN), a ligand for toll-like receptor (TLR) 2, and to poly I:C, a ligand for TLR3, with delayed, sustained secretion of PGE2. PGN induces expression of mRNAfor both PGHS-2 and microsomal PGE2 synthase-1 (M-PGES-1), along with the corresponding proteins. Notably, exogenous PGE2 markedly inhibits cysLT and PGD2 generation by hMCs, and substantially inhibits the production of tumor necrosis factor (TNF-a) and IL-5 in response to either FcsRI crosslinkage or stimulation with PGN. We hypothesize that 1. Innate and adaptive immune responses elicit contrasting profiles of eicosanoid generation from MCs, with PGHS-2 and M-PGES-1 being inducible in each;2. PGE&through more than one EP receptor, limits consequences of MC activation in an autocrine orparacrine manner;and 3. AIA involves dysregulation of inducible PGE2 synthase function. We therefore propose the following Specific Aims: 1) to define the terminal synthases responsible for the sustained phase of PGE2 synthesis in hMCs activated through different transmembrane stimuli, 2) to define the receptors and biochemical mechanisms responsible for PGE2-mediated inhibition of hMC activation, and 3) to determine whether defects in the inducible PGE2 synthesis system underlie AIA.
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