title: Proinflammatory actions of thromboxane receptors to enhance cellular immune responses.
abstract: Metabolism of arachidonic acid by the cyclo-oxygenase (COX) pathway generates a family of prostanoid mediators. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX, thereby reducing prostanoid synthesis. The efficacy of these agents in reducing inflammation suggests a dominant proinflammatory role for the COX pathway. However, the actions of COX metabolites are complex, and certain prostanoids, such as PGE(2), in some circumstances actually inhibit immune and inflammatory responses. In these studies, we examine the hypothesis that anti-inflammatory actions of NSAIDs may be due, in part, to inhibition of thromboxane A(2) synthesis. To study the immunoregulatory actions of thromboxane A(2), we used mice with a targeted disruption of the gene encoding the thromboxane-prostanoid (TP) receptor. Both mitogen-induced responses and cellular responses to alloantigen were substantially reduced in TP(-/-) spleen cells. Similar attenuation was observed with pharmacological inhibition of TP signaling in wild-type splenocytes, suggesting that reduced responsiveness was not due to subtle developmental abnormalities in the TP-deficient mice. The absence of TP receptors reduced immune-mediated tissue injury following cardiac transplant rejection, an in vivo model of intense inflammation. Taken together, these findings show that thromboxane augments cellular immune responses and inflammatory tissue injury. Specific inhibition of the TP receptor may provide a more precise approach to limit inflammation without some of the untoward effects associated with NSAIDs.
authors.affiliation: Division of Nephrology, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC 27705, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Thomas
authors.forename: Paulo N
authors.initials: PN
authors.lastname: Rocha
authors.forename: Chandra
authors.initials: C
authors.lastname: Nataraj
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Robinson
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spurney
authors.forename: Beverly H
authors.initials: BH
authors.lastname: Koller
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000276:Adjuvants, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017482:Receptors, Thromboxane / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012260:Ribonucleases / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D017482:Receptors, Thromboxane; D012260:Ribonucleases; D013930:Thromboxane-A Synthase