Lysophosphatidic acid induces chemotaxis, oxygen radical production, CD11b up-regulation, Ca2+ mobilization, and actin reorganization in human eosinophils via pertussis toxin-sensitive G proteins.
Lysophosphatidic acid (LPA) is a bioactive lipid mediator, which is generated by secretory type II phospholipase A(2) and is thought to play a major role in the pathogenesis of atopic diseases. In this study, the biological activity of LPA on human eosinophils was characterized. We showed by reverse transcription and PCR that human eosinophils express the mRNA of the LPA receptors endothelial differentiation gene (EDG)-2 and EDG-7. Experiments revealed that LPA has chemotactic activity toward eosinophils, stimulates the production of reactive oxygen metabolites, and induces up-regulation of the integrin CD11b. Signal pathway measurements indicated Ca(2+)-mobilization from intracellular stores and transient actin polymerization upon stimulation with LPA. Cell responses elicited by LPA were inhibited by pertussis toxin indicating that in eosinophils the LPA receptor(s), presumably EDG-2 and/or EDG-7, are coupled to G(i/o) proteins. Moreover, LPA-induced activation of eosinophils could be completely blocked by the EDG-2/EDG-7 antagonist diacylglycerol pyrophosphate. In addition, at optimal doses the changes induced by LPA were comparable to those obtained by the other well-characterized chemotaxins. These results indicate that LPA is a strong chemotaxin and activator of eosinophils. These findings point to a novel role of LPA in the pathogenesis of diseases with eosinophilic inflammation such as atopic diseases as chemotaxin as well as activator of proinflammatory effector functions.
Idzko
Marco
M
Department of Pneumonology and Experimental Dermatology, University of Freiburg, Freiburg, Germany.
Laut
Martin
M
Panther
Elisabeth
E
Sorichter
Stephan
S
Dürk
Thorsten
T
Fluhr
Joachim W
JW
Herouy
Yared
Y
Mockenhaupt
Maja
M
Myrtek
Daniel
D
Elsner
Peter
P
Norgauer
Johannes
J
D000199:Actins / Q000378:metabolism*; D039481:CD11b Antigen / Q000096:biosynthesis*; D020013:Calcium Signaling / Q000276:immunology*; D002631:Chemotactic Factors, Eosinophil / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D011756:Diphosphates / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000502:physiology*; D037342:Pertussis Toxin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid; D016897:Respiratory Burst / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
D000199:Actins; D039481:CD11b Antigen; D002631:Chemotactic Factors, Eosinophil; D011756:Diphosphates; D008246:Lysophospholipids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; C408642:diacylglycerol pyrophosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D005990:Glycerol; C032881:lysophosphatidic acid