Niflumic acid renders dendritic cells tolerogenic and up-regulates inhibitory molecules ILT3 and ILT4.
Niflumic acid is a member of non-steroidal anti-inflammatory agents, from which aspirin was recently shown to inhibit maturation of human-monocyte derived dendritic cells (DCs). DCs are crucial regulators of the immune response, capable of inducing immunity as well as tolerance. In our in vitro study we showed a tolerogenic effect of NFA on phenotype and function of LPS-matured monocyte-derived DCs. Different drug concentrations dose-dependently down-regulated the expression of co-stimulatory molecules, particularly CD80 and lowered the expression of dendritic cell marker CD1a. Opposingly, the expressions of two inhibitory surface molecules, associated with tolerogenic DCs, immunoglobulin-like transcripts (ILT)3 and ILT4 were induced in treated DCs. The levels of TNFalpha production by NFA-treated DCs did not change significantly compared to controls, whereas the IL-12p70 and IL-10 production was completely abrogated at higher drug concentrations. However, at lower drug concentrations, the production of IL-12p70 was increased. There were no significant differences in the uptake of FITC labeled dextran by treated DCs compared to untreated cells. In allogeneic cultures with whole CD4+ T cells, dendritic cells differentiated in the presence of NFA appeared poor stimulators of CD4+ T-cell proliferation, even compared to immature DCs (iDCs). These results indicate the immunosuppressive properties of NFA, which may be therapeutically useful in controlling chronic immune and/or inflammatory diseases, by modulating DC characteristics towards tolerogenic DCs.
Svajger
Urban
U
Tissue Typing Center, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia. urban.svajger@ztm.si <urban.svajger@ztm.si>
Vidmar
Alenka
A
Jeras
Matjaz
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004705:Endocytosis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000502:physiology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics*; D009544:Niflumic Acid / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics*; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018118:Chloride Channels; D016861:Cyclooxygenase Inhibitors; D007166:Immunosuppressive Agents; C491341:LILRB2 protein, human; C107907:LILRB4 protein, human; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D016753:Interleukin-10; D018664:Interleukin-12; D009544:Niflumic Acid