title: Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells.
abstract: Aspirin is the most commonly used analgesic and antiinflammatory agent. In this study, at physiological concentrations, it profoundly inhibited CD40, CD80, CD86, and MHC class II expression on murine, GM-CSF + IL-4 stimulated, bone marrow-derived myeloid dendritic cells (DC). CD11c and MHC class I expression were unaffected. The inhibitory action was dose dependent and was evident at concentrations higher than those necessary to inhibit PG synthesis. Experiments with indomethacin revealed that the effects of aspirin on DC maturation were cyclooxygenase independent. Nuclear extracts of purified, aspirin-treated DC revealed a decreased NF-kappaB DNA-binding activity, whereas Ab supershift analysis indicated that aspirin targeted primarily NF-kappaB p50. Unexpectedly, aspirin promoted the generation of CD11c+ DC, due to apparent suppression of granulocyte development. The morphological and ultrastructural appearance of aspirin-treated cells was consistent with immaturity. Aspirin-treated DC were highly efficient at Ag capture, via both mannose receptor-mediated endocytosis and macropinocytosis. By contrast, they were poor stimulators of naive allogeneic T cell proliferation and induced lower levels of IL-2 in responding T cells. They also exhibited impaired IL-12 expression and did not produce IL-10 after LPS stimulation. Assessment of the in vivo function of aspirin-treated DC, pulsed with the hapten trinitrobenzenesulfonic acid, revealed an inability to induce normal cell-mediated contact hypersensitivity, despite the ability of the cells to migrate to T cell areas of draining lymphoid tissue. These data provide new insight into the immunopharmacology of aspirin and suggest a novel approach to the manipulation of DC for therapeutic application.
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hackstein
authors.forename: A E
authors.initials: AE
authors.lastname: Morelli
authors.forename: A T
authors.initials: AT
authors.lastname: Larregina
authors.forename: R W
authors.initials: RW
authors.lastname: Ganster
authors.forename: G D
authors.initials: GD
authors.lastname: Papworth
authors.forename: A J
authors.initials: AJ
authors.lastname: Logar
authors.forename: S C
authors.initials: SC
authors.lastname: Watkins
authors.forename: L D
authors.initials: LD
authors.lastname: Falo
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D003877:Dermatitis, Contact / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D016167:Integrin alphaXbeta2 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D016167:Integrin alphaXbeta2; D007376:Interleukin-2; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D016753:Interleukin-10; D018664:Interleukin-12; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin