Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils.
We investigated the actions of a panel of nonsteroidal anti-inflammatory drugs on eosinophils, basophils, neutrophils, and monocytes. Indomethacin alone was a potent and selective inducer of eosinophil and basophil shape change. In eosinophils, indomethacin induced chemotaxis, CD11b up-regulation, respiratory burst, and L-selectin shedding but did not cause up-regulation of CD63 expression. Pretreatment of eosinophils with indomethacin also enhanced subsequent eosinophil shape change induced by eotaxin, although treatment with higher concentrations of indomethacin resulted in a decrease in the expression of the major eosinophil chemokine receptor, CCR3. Indomethacin activities and cell selectivity closely resembled those of prostaglandin D(2) (PGD(2)). Eosinophil shape change in response to eotaxin was inhibited by pertussis toxin, but indomethacin- and PGD(2)-induced shape change responses were not. Treatment of eosinophils with specific inhibitors of phospholipase C (U-73122), phosphatidylinositol 3-kinase (LY-294002), and p38 mitogen-activated protein kinase (SB-202190) revealed roles for these pathways in indomethacin signaling. Indomethacin and its analogues may therefore provide a structural basis from which selective PGD(2) receptor small molecule antagonists may be designed and which may have utility in the treatment of allergic inflammatory disease.
Stubbs
Victoria E L
VE
Leukocyte Biology Section, Biomedical Sciences Division, Imperial College Faculty of Medicine, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AZ, United Kingdom.
Schratl
Petra
P
Hartnell
Adele
A
Williams
Timothy J
TJ
Peskar
Bernhard A
BA
Heinemann
Akos
A
Sabroe
Ian
I
D015703:Antigens, CD / Q000378:metabolism; D001491:Basophils / Q000187:drug effects / Q000378:metabolism*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002867:Chromones; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines; D037342:Pertussis Toxin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D015230:Prostaglandin D2 / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D016897:Respiratory Burst; D060149:Tetraspanin 30; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D015854:Up-Regulation; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; C515456:CCL11 protein, human; C554586:CD63 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002867:Chromones; D004791:Enzyme Inhibitors; D004963:Estrenes; D007093:Imidazoles; D016177:Macrophage-1 Antigen; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines; D011760:Pyrrolidinones; D060149:Tetraspanin 30; D010566:Virulence Factors, Bordetella; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D015230:Prostaglandin D2; D007213:Indomethacin