Cyclooxygenase-independent inhibition of dendritic cell maturation by aspirin.
When immature human myeloid dendritic cells were differentiated in vitro in the presence of aspirin, they were unable to stimulate T-cell proliferation. Aspirin and its major metabolite salicylate changed the surface marker phenotype of dendritic cells. The drugs particularly suppressed the levels of CD83 and the secreted p40 unit of interleukin-12 (IL-12), both markers of mature dendritic cells; 50% inhibitory concentration (IC50) values were 2.5 mM, a concentration more than 100 times greater than the concentration at mid-point inhibition (ID50) value for inhibition of prostaglandin synthesis. Concomitantly, the levels of CD14, a marker of monocytes/macrophages, increased above the levels found in immature dendritic cells. Cyclooxygenase inhibitors ketoprofen, indomethacin and NS-398 had no effect at concentrations more than a thousand-fold higher than their IC50 values. The effects were independent of the presence of prostaglandin E2 in the medium. Salicylates suppressed activation of the nuclear transcription factor kappaB, which regulates dendritic cell differentiation, but their effects on mature dendritic cells were negligible. Hence, aspirin inhibits dendritic cell function by inhibiting their terminal differentiation at concentrations achieved in the blood of patients chronically treated with high-dose aspirin.
Matasic
R
R
Stem Cell Laboratory, Mayo Clinic Cancer Center, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
Dietz
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AB
Vuk-Pavlovic
S
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D020156:Salicylic Acid / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D018664:Interleukin-12; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D020156:Salicylic Acid; D001241:Aspirin