Mast cells (MCs) to respond to activation by innate stimuli or cross linking of the high-affinity receptor for IgE (FceRI) by generating eicosanoids, particularly the cysteinyl leukotrienes (cysLTs) and prostaglandin (PG) D2, providing a direct link to the inflammatory processes in bronchial asthma. While the role of cysLTs in bronchial asthma is established by the efficacy of therapeutic agents that block their synthesis or their action at the type 1 (CysLT-i) receptor, comparable evidence for PGD2 awaits development of specific inhibitors for human use. Our Preliminary studies now reveal that PGD2 unexpectedly suppresses LTC4 synthase (LTC4S) and LTC4 generation by mouse bone marrow-derived MCs (mBMMCs), and that a microbial signal, eptidoglycan (PGN), induces the expression of LTC4S (but not hematopoietic PGD2 synthase) by mBMMCs. Unlike IL-4, PGN upregulates LTC4S by a signal transducer activator of transcription (STAT)6 independent signaling pathway that likely involves nuclear factor KB (NF-icB) and other Toll-like receptor (TLR)-dependent signals. We hypothesize that (1) that PGD2 inhibits LTC4S function by a DP2 receptor-mediated signal directed predominantly to a post translational mechanism, that PGN upregulates LTC4S expression through NF-KB-dependent transcription and that the PGD2 mediated down regulation of LTC4S action will be dominant over the enhancement action of PGN;(2) that in allergen challenge models of pulmonary inflammation, CysLT1 is more important in the inflammatory response and CysLT2 is more relavent to pulmonary remodeling, and that MC-derived PGD2 and PGE2, through suppression of LTC4S, will counter the effects of cysLTs;and (3) that LTC4S functions as homotrimer with each monomer containing four alpha helixes, and that Arg-51 and Tyr-93 are involved in catalysis while lle-27, Val-35, Val-49, Arg-51, Ala-52, Asn-55, Tyr-59, Tyr-93, Tyr-97, and Ala-112 form the binding sites for LTA4 and GSH. We therefore propose the following Specific Aims: 1) To elucidate the mechanism by which PGN upregulates and PGD2 downregulates the expression of LTC4S in mBMMCs;2) To examine the in vivo role of LTC4 and PGD2 in mast cell dependent models of airway inflammation and in chronic models with remodeling of airways;and 3) To determine the three-dimensional structure of human LTC4S by X-ray crystallography.

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Liu, Tao; Barrett, Nora A; Kanaoka, Yoshihide et al. (2018) Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. J Immunol 200:915-927
Liu, Tao; Garofalo, Denise; Feng, Chunli et al. (2015) Platelet-driven leukotriene C4-mediated airway inflammation in mice is aspirin-sensitive and depends on T prostanoid receptors. J Immunol 194:5061-8
Laidlaw, Tanya M; Cutler, Anya J; Kidder, Molly S et al. (2014) Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 133:1692-701.e3
Fanning, Laura B; Buckley, Carolyn C; Xing, Wei et al. (2013) Downregulation of key early events in the mobilization of antigen-bearing dendritic cells by leukocyte immunoglobulin-like Receptor B4 in a mouse model of allergic pulmonary inflammation. PLoS One 8:e57007
Ohta, Shin; Imamura, Mitsuru; Xing, Wei et al. (2013) Group V secretory phospholipase A2 is involved in macrophage activation and is sufficient for macrophage effector functions in allergic pulmonary inflammation. J Immunol 190:5927-38
Cummings, Hannah E; Liu, Tao; Feng, Chunli et al. (2013) Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor. J Immunol 191:5807-10
Liu, Tao; Laidlaw, Tanya M; Katz, Howard R et al. (2013) Prostaglandin E2 deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes. Proc Natl Acad Sci U S A 110:16987-92
Laidlaw, Tanya M; Kidder, Molly S; Bhattacharyya, Neil et al. (2012) Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 119:3790-8
Simarro, Maria; Giannattasio, Giorgio; Xing, Wei et al. (2012) The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of Th2 and Th17 responses driving pulmonary inflammation induced by exposure to house dust mite. Immunol Lett 146:8-14
Cozzi, Emily; Ackerman, Kate G; Lundequist, Anders et al. (2011) The naive airway hyperresponsiveness of the A/J mouse is Kit-mediated. Proc Natl Acad Sci U S A 108:12787-92

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