Cys-LTs are potent bronchoconstrictors, powerful inducers of vascular leakage andpotentiators of airway hyperresponsiveness and play an essential role in asthma. Theimportance of MCs as effector cells in asthma makes it imperative to understand thebasic mechanisms by which the cys-LTs regulate the function of MCs. LTE4, though themost abundant and stable of the cys-LTs, is a weak, partial agonist for the knownCysLTRs, but induces unique responses in vivo that cannot be recapitulated by LTC4 orLTD4. Our preliminary Studies indicate that LTE4 potently stimulates cell proliferation,cytokine production, and COX-2-dependent PGD2 generation in hMCs that are notexplained by the conventional CysLTRs. Blocking PPAR or P2Y12 receptor abrogatesLTE4-induced MIP-1 generation as well as PGD2 response in LAD2 cells.Complimenting this, in vivo LTE4 unlike LTD4 amplifies mucosal inflammation inducedby 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. Inthe present grant, we hypothesise that 1. Different PKCs mediate CysLTR-mediatedresponses and 2. LTE4 differs from its precursors by stimulating strong signalingthrough a PPAR- -dependent mechanism and its responses involve contributions fromCysLT1-like receptors, P2Y12 receptor and PPAR- . We attempt to identify signalingintermediates involved in these responses and analyze the effects on mast cellfunctions. Both cys-LTs and the major MC-derived eicosanoid, PGD2, are abundant inthe pathology of asthma in humans both induce and amplify experimental allergicpulmonary inflammation in mice. Although these mediator classes participate in thesame contexts, little is known regarding cross-regulation between them. The fact thatcys-LTs prominently regulate MC development in mucosal inflammation suggests thatlocally-derived cys-LTs could control PGD2 production through actions on MCs. Ifcorrect, this could carry substantial pathogenetic and therapeutic implications forasthma and allergic diseases in particular and control of Th2 responses.
This proposal seeks to determine how a common lipid mediator leukotriene E4 can regulate the activation of mast cells, an 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.
| Kondeti, Vinay; Al-Azzam, Nosayba; Duah, Ernest et al. (2016) Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3. J Allergy Clin Immunol 137:289-298 |
| Al-Azzam, Nosayba; Kondeti, Vinay; Duah, Ernest et al. (2015) Modulation of mast cell proliferative and inflammatory responses by leukotriene d4 and stem cell factor signaling interactions. J Cell Physiol 230:595-602 |
| Kondeti, Vinay; Duah, Ernest; Al-Azzam, Nosayba et al. (2013) Differential regulation of cysteinyl leukotriene receptor signaling by protein kinase C in human mast cells. PLoS One 8:e71536 |
