Cysteinyl leukotriene signaling in proliferation, cytokine production and PGD2 ge

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DESCRIPTION (provided by applicant): Cys-LTs are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness and play an essential role in asthma. The importance of MCs as effector cells in asthma makes it imperative to understand the basic mechanisms by which the cys-LTs regulate the function of MCs. LTE4, though the most abundant and stable of the cys-LTs, is a weak, partial agonist for the known CysLTRs, but induces unique responses in vivo that cannot be recapitulated by LTC4 or LTD4. Our preliminary Studies indicate that LTE4 potently stimulates cell proliferation, cytokine production, and COX-2-dependent PGD2 generation in hMCs that are not explained by the conventional CysLTRs. Blocking PPAR3 or P2Y12 receptor abrogates LTE4-induced MIP-12 generation as well as PGD2 response in LAD2 cells. Complimenting this, in vivo LTE4 unlike LTD4 amplifies mucosal inflammation induced by low-dose allergen in sensitized BALB/c mice that is mediated by the P2Y12 receptor. This suggest that contrary to the widely held belief that LTD4 is the major effector cys- LT, LTE4 may have a central and unique role in mucosal and vascular inflammation. In the present grant, we hypothesize that 1. Different PKCs mediate CysLTR-mediated responses and 2. LTE4 differs from its precursors by stimulating strong signaling through a PPAR-3-dependent mechanism and its responses involve contributions from CysLT1-like receptors, P2Y12 receptor and PPAR-3. We attempt to identify signaling intermediates involved in these responses and analyze the effects on mast cell functions. Both cys-LTs and the major MC-derived eicosanoid, PGD2, are abundant in the pathology of asthma in humans both induce and amplify experimental allergic pulmonary inflammation in mice. Although these mediator classes participate in the same contexts, little is known regarding cross-regulation between them. The fact that cys-LTs prominently regulate MC development in mucosal inflammation suggests that locally-derived cys-LTs could control PGD2 production through actions on MCs. If correct, this could carry substantial pathogenetic and therapeutic implications for asthma and allergic diseases in particular and control of Th2 responses. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine how a common lipid mediator leukotriene E4 can regulate the activation of mast cells, important cells mediating the inflammatory responses in response to allergens and infectious agents. Studying this could help us in better understanding and treatment strategies for asthma and other allergies.