Sitagliptin Induces Tolerogenic Human Dendritic Cells

被引：1

作者：

Drakul, Marija ^{[1
]}

Tomic, Sergej ^{[2
]}

Bekic, Marina ^{[2
]}

Mihajlovic, Dusan ^{[1
]}

Vasiljevic, Milos ^{[1
]}

Rakocevic, Sara ^{[1
]}

Dokic, Jelena ^{[3
]}

Popovic, Nikola ^{[3
]}

Bokonjic, Dejan ^{[1
]}

Colic, Miodrag ^{[1
,4
]}

机构：

[1] Univ East Sarajevo, Med Fac Foca, Foca 73300, Bosnia & Herceg

[2] Univ Belgrade, Inst Applicat Nucl Energy, Belgrade 11000, Serbia

[3] Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade 11000, Serbia

[4] Serbian Acad Arts & Sci, Belgrade 11000, Serbia

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2023年 / 24卷 / 23期

关键词：

dipeptidyl peptidase 4 inhibitors; dendritic cells; tolerance; CD26; expression; regulatory T cells; NF-KAPPA-B; P38 MAPK INHIBITOR; PEPTIDASE; 4; DPP4; TH17; CELLS; T-CELLS; CD26; MATURATION; DIFFERENTIATION; TH2; ACTIVATION;

D O I：

10.3390/ijms242316829

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-gamma treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 mu 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-beta, 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-beta) 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-beta+ 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.

引用

页数：24