Cysteinyl-LTs (cysteinyl-LTs), LTC4, LTD4 and LTE4, are potent inflammatory mediators and bronchoconstrictors known to play an important role in asthma and allergic rhinitis. Until now, two receptor subtypes for cysteinyl-LTs have been cloned, namely CysLT1 and CysLT2, both belonging to the rhodopsin family of the G-protein-coupled receptors (GPCRs) superfamily and, in particular, to the purine receptor cluster. P2Y receptors are GPCRs responsive to both adenine (ATP, ADP) and uracil (UTP, UDP) nucleotides, or to sugar nucleotides (UDP-glucose and UDP-galactose) and eight P2Y subtypes are currently recognized, i.e. P2Y1-14. These receptors are widely distributed in human tissues, and important pathophysiological roles also in respiratory functions have been suggested. Since both mediators accumulate at sites of inflammation, and inflammatory cells express both classes of receptors, their responses are likely to be cross-regulated. We have demonstrated that activation of P2Y receptors with ATP, UDP or UTP induced CysLT1 receptor heterologous desensitization. Conversely, LTD4-induced CysLT1 receptor activation had no effect on P2Y receptor responses, suggesting that the latter have a hierarchy in producing desensitizing signals. Interestingly, montelukast, pranlukast and zafirlukast, orally-active leukotriene antagonists (LTRAs) selective for the CysLT1 receptor subtype, inhibited both UDP- and UTP-induced activation of phospholipase C and intracellular Ca2+ mobilization in a non-competitive manner, as well as UDP-induced IL-8 production. Furthermore, administration of LTE4 to the airways of sensitized mice has been demonstrated to potentiate eosinophilia, goblet cell metaplasia, and expression of IL-13 in response to low-dose aerosolized allergen, an effect abrogated by P2Y12 knock-down or platelet depletion. All together these data not only point to a cross-talk between the CysLT and the P2Y recepor systems, but also suggest that it might be some common molecular target mediating nucleotide- and cysteinyl-LT-induced signaling, something that may have a profound physiological implication in the regulation of responses at the sites of inflammation. In addition, these data also demonstrate non-CysLT1-mediated antiinflammatory effect of clinically used antiasthmatic drugs, suggesting activities potentially relevant for interpatient variability in response to treatment. Higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a new strategy for finding more efficient therapy for bronchial asthma.
Cross-talk Between Cysteinyl-Leukotriene and Purinergic Receptors / G. Rovati. ((Intervento presentato al 67. convegno American Academy of Allergy, Asthma and Immunology Annual Meeting tenutosi a San Francisco nel 2011.
|Titolo:||Cross-talk Between Cysteinyl-Leukotriene and Purinergic Receptors|
ROVATI, GIANENRICO (Primo)
|Data di pubblicazione:||20-mar-2011|
|Parole Chiave:||cysteinyl-leukotrienes ; CYSLT ; purines|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Enti collegati al convegno:||American Academy of Allergy, Asthma and Immunology|
|Citazione:||Cross-talk Between Cysteinyl-Leukotriene and Purinergic Receptors / G. Rovati. ((Intervento presentato al 67. convegno American Academy of Allergy, Asthma and Immunology Annual Meeting tenutosi a San Francisco nel 2011.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|