E. Böhm, G. Sturm, I. Weiglhofer
Feb 27, 2004
Citations
2
Influential Citations
101
Citations
Quality indicators
Journal
Journal of Biological Chemistry
Abstract
Thromboxane (TX) A2, a cyclooxygenase-derived mediator involved in allergic responses, is rapidly converted in vivo to a stable metabolite, 11-dehydro-TXB2, which is considered to be biologically inactive. In this study, we found that 11-dehydro-TXB2, but not the TXA2 analogue U46,619 or TXB2, activated eosinophils and basophils, as assayed by flow cytometric shape change. 11-Dehydro-TXB2 was also chemotactic for eosinophils but did not induce, nor inhibit, platelet aggregation. Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) is an important chemoattractant receptor expressed by eosinophils, basophils, and TH2 lymphocytes, and prostaglandin (PG)D2 has been shown to be its principal ligand. 11-Dehydro-TXB2 induced calcium flux mainly from intracellular stores in eosinophils, and this response was desensitized after stimulation with PGD2 but not other eosinophil chemoattractants. Shape change responses of eosinophils and basophils to 11-dehydro-TXB2 were inhibited by the thromboxane (TP)/CRTH2 receptor antagonist ramatroban, but not the selective TP antagonist SQ29,548, and were insensitive to pertussis toxin. The phospholipase C inhibitor U73,122 attenuated both 11-dehydro-TXB2- and PGD2-induced shape change. 11-Dehydro-TXB2 also induced the chemotaxis of BaF/3 cells transfected with hCRTH2 but not naive BaF/3 cells. At a threshold concentration, 11-dehydro-TXB2 had no antagonistic effect on CRTH2-mediated responses as induced by PGD2. These data show that 11-dehydro-TXB2 is a full agonist of the CRTH2 receptor and hence might cause CRTH2 activation in cellular contexts where PGD-synthase is not present. Given its production in the allergic lung, antagonism of the 11-dehydro-TXB2/CRTH2axis may be of therapeutic relevance.