Sitagliptin Induces Tolerogenic Human Dendritic Cells

Author:

Drakul Marija1,Tomić Sergej2ORCID,Bekić Marina2ORCID,Mihajlović Dušan1ORCID,Vasiljević Miloš1,Rakočević Sara1,Đokić Jelena3,Popović Nikola3ORCID,Bokonjić Dejan1ORCID,Čolić Miodrag14

Affiliation:

1. Medical Faculty Foca, University of East Sarajevo, 73300 Foča, R. Srpska, Bosnia and Herzegovina

2. Institute for the Application of Nuclear Energy, University of Belgrade, 11000 Belgrade, Serbia

3. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia

4. Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia

Abstract

Sitagliptin, 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-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/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-β, 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-β) 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-β+ 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.

Funder

University of East Sarajevo, Medical Faculty Foča, Foča, Bosnia and Herzegovina

Ministry of Science, Technological Development and Innovation, Republic of Serbia

Serbian Academy of Sciences and Arts

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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