Sitagliptin Induces Tolerogenic Human Dendritic Cells

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dc.citation.spage16829
dc.citation.volume24
dc.contributor.authorDrakul, Marija
dc.contributor.authorTomić, Sergej
dc.contributor.authorBekić, Marina
dc.contributor.authorMihajlović, Dušan
dc.contributor.authorVasiljević, Miloš
dc.contributor.authorRakočević, Sara
dc.contributor.authorÐokić, Jelena
dc.contributor.authorPopović, Nikola
dc.contributor.authorBokonjić, Dejan
dc.contributor.authorČolić, Miodrag
dc.date.accessioned2024-11-20T13:03:18Z
dc.date.available2024-11-20T13:03:18Z
dc.date.issued2023
dc.description.abstractSitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-y treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 g/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL- , IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF- ) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF- + Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection.
dc.identifier.doi10.3390/ijms242316829
dc.identifier.urihttps://vaseljena.ues.rs.ba/handle/123456789/1324
dc.language.isoen
dc.publisherMDPI
dc.sourceInternational Journal of Molecular Sciences
dc.subjectdipeptidyl peptidase 4 inhibitors; dendritic cells; tolerance; CD26 expression; regulatory T cells
dc.titleSitagliptin Induces Tolerogenic Human Dendritic Cells
dc.typeArticle
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