Sitagliptin Induces Tolerogenic Human Dendritic Cells
Authors
Drakul, MarijaTomić, Sergej
Bekić, Marina
Mihajlović, Dušan
Vasiljević, Miloš
Rakočević, Sara
Đokić, Jelena
Popović, Nikola
Bokonjić, Dejan
Čolić, Miodrag
Article (Published version)
Metadata
Show full item recordAbstract
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.
Keywords:
CD26 expression / dendritic cells / dipeptidyl peptidase 4 inhibitors / regulatory T cells / toleranceSource:
International Journal of Molecular Sciences, 2023, 24, 23, 16829-Publisher:
- MDPI
Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200019 (University of Belgrade, Institute for the Application of Nuclear Energy - INEP) (RS-MESTD-inst-2020-200019)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200042 (University of Belgrade, Institute of Molecular Genetics and Genetic Engineering) (RS-MESTD-inst-2020-200042)
- Serbian Academy of Sciences and Arts (project F115)
- University of East Sarajevo, Medical Faculty Foca, Foca, Bosnia and Herzegovina, (project UIS/MFF: I.1.20-22)
Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Drakul, Marija AU - Tomić, Sergej AU - Bekić, Marina AU - Mihajlović, Dušan AU - Vasiljević, Miloš AU - Rakočević, Sara AU - Đokić, Jelena AU - Popović, Nikola AU - Bokonjić, Dejan AU - Čolić, Miodrag PY - 2023 UR - https://www.mdpi.com/1422-0067/24/23/16829 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2220 AB - 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. PB - MDPI T2 - International Journal of Molecular Sciences T2 - International Journal of Molecular Sciences T1 - Sitagliptin Induces Tolerogenic Human Dendritic Cells IS - 23 SP - 16829 VL - 24 DO - 10.3390/ijms242316829 ER -
@article{ author = "Drakul, Marija and Tomić, Sergej and Bekić, Marina and Mihajlović, Dušan and Vasiljević, Miloš and Rakočević, Sara and Đokić, Jelena and Popović, Nikola and Bokonjić, Dejan and Čolić, Miodrag", year = "2023", 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.", publisher = "MDPI", journal = "International Journal of Molecular Sciences, International Journal of Molecular Sciences", title = "Sitagliptin Induces Tolerogenic Human Dendritic Cells", number = "23", pages = "16829", volume = "24", doi = "10.3390/ijms242316829" }
Drakul, M., Tomić, S., Bekić, M., Mihajlović, D., Vasiljević, M., Rakočević, S., Đokić, J., Popović, N., Bokonjić, D.,& Čolić, M.. (2023). Sitagliptin Induces Tolerogenic Human Dendritic Cells. in International Journal of Molecular Sciences MDPI., 24(23), 16829. https://doi.org/10.3390/ijms242316829
Drakul M, Tomić S, Bekić M, Mihajlović D, Vasiljević M, Rakočević S, Đokić J, Popović N, Bokonjić D, Čolić M. Sitagliptin Induces Tolerogenic Human Dendritic Cells. in International Journal of Molecular Sciences. 2023;24(23):16829. doi:10.3390/ijms242316829 .
Drakul, Marija, Tomić, Sergej, Bekić, Marina, Mihajlović, Dušan, Vasiljević, Miloš, Rakočević, Sara, Đokić, Jelena, Popović, Nikola, Bokonjić, Dejan, Čolić, Miodrag, "Sitagliptin Induces Tolerogenic Human Dendritic Cells" in International Journal of Molecular Sciences, 24, no. 23 (2023):16829, https://doi.org/10.3390/ijms242316829 . .