Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor.
Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC4, LTD4, and LTE4), only LTE4 is stable and abundant in vivo. Although LTE4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT1R and CysLT2R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)-reactive purinergic (P2Y12) receptor is required for LTE4-mediated pulmonary inflammation. P2Y12 receptor expression permits LTE4-induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D2 production by LAD2 cells, a human mast cell line. P2Y12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE4 but not for direct binding of LTE4, suggesting that P2Y12 complexes with another receptor to recognize LTE4. Administration of LTE4 to the airways of sensitized mice potentiates eosinophilia, goblet cell metaplasia, and expression of interleukin-13 in response to low-dose aerosolized allergen. These responses persist in mice lacking both CysLT1R and CysLT2R but not in mice lacking P2Y12 receptors. The effects of LTE4 on P2Y12 in the airway were abrogated by platelet depletion. Thus, the P2Y12 receptor is required for proinflammatory actions of the stable abundant mediator LTE4 and is a novel potential therapeutic target for asthma.
Paruchuri
Sailaja
S
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Tashimo
Hiroyuki
H
Feng
Chunli
C
Maekawa
Akiko
A
Xing
Wei
W
Jiang
Yongfeng
Y
Kanaoka
Yoshihide
Y
Conley
Pamela
P
Boyce
Joshua A
JA
D000485:Allergens / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology; D001980:Bronchi / Q000276:immunology / Q000473:pathology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D020397:Goblet Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D017999:Leukotriene E4; D008407:Mast Cells / Q000276:immunology; D008679:Metaplasia; D051379:Mice; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D058919:Purinergic P2 Receptor Antagonists; D018077:Receptors, Leukotriene / Q000276:immunology; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins / Q000378:metabolism
D000485:Allergens; D039741:Antigens, Dermatophagoides; C548576:P2RY12 protein, human; C548577:P2ry12 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018077:Receptors, Leukotriene; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins; D017999:Leukotriene E4; C083169:leukotriene D4 receptor