TY  - 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 . .

TY  - JOUR
AU  - Bekić, Marina
AU  - Radanović, Marina
AU  - Đokić, Jelena
AU  - Tomić, Sergej
AU  - Eraković, Mile
AU  - Radojević, Dušan
AU  - Duka, Milos
AU  - Marković, Dejan
AU  - Marković, Milan
AU  - Ismaili, Bashkim
AU  - Bokonjić, Dejan
AU  - Čolić, Miodrag
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1558
AB  - Gingiva-Derived Mesenchymal Stromal Cells (GMSCs) have been shown to play an important role in periodontitis. However, how P. gingivalis, one of the key etiological agents of the disease, affects healthy (H)- and periodontitis (P)-GMSCs is unknown. To address this problem, we established 10 H-GMSC and 12 P-GMSC lines. No significant differences in morphology, differentiation into chondroblasts and adipocytes, expression of characteristic MSCS markers, including pericyte antigens NG2 and PDGFR, were observed between H- and P-GMSC lines. However, proliferation, cell size and osteogenic potential were higher in P-GMSCs, in contrast to their lower ability to suppress mononuclear cell proliferation. P. gingivalis up-regulated the mRNA expression of IL-6, IL-8, MCP-1, GRO-alpha, RANTES, TLR-2, HIF-1 alpha, OPG, MMP-3, SDF-1, HGF and IP-10 in P-GMSCs, whereas only IL-6, MCP-1 and GRO-alpha were up-regulated in H-GMSCs. The expression of MCP-1, RANTES, IP-10 and HGF was significantly higher in P-GMSCs compared to H-GMSCs, but IDO1 was lower. No significant changes in the expression of TLR-3, TLR-4, TGF-beta, LAP, IGFBP4 and TIMP-1 were observed in both types of GMSCs. In conclusion, our results suggest that P-GMSCs retain their pro-inflammatory properties in culture, exhibit lower immunosuppressive potential than their healthy counterparts, and impaired regeneration-associated gene induction in culture. All these functions are potentiated significantly by P. gingivalis treatment.
PB  - MDPI, Basel
T2  - International Journal of Molecular Sciences
T1  - Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis
IS  - 7
VL  - 23
DO  - 10.3390/ijms23073510
ER  - 

@article{
author = "Bekić, Marina and Radanović, Marina and Đokić, Jelena and Tomić, Sergej and Eraković, Mile and Radojević, Dušan and Duka, Milos and Marković, Dejan and Marković, Milan and Ismaili, Bashkim and Bokonjić, Dejan and Čolić, Miodrag",
year = "2022",
abstract = "Gingiva-Derived Mesenchymal Stromal Cells (GMSCs) have been shown to play an important role in periodontitis. However, how P. gingivalis, one of the key etiological agents of the disease, affects healthy (H)- and periodontitis (P)-GMSCs is unknown. To address this problem, we established 10 H-GMSC and 12 P-GMSC lines. No significant differences in morphology, differentiation into chondroblasts and adipocytes, expression of characteristic MSCS markers, including pericyte antigens NG2 and PDGFR, were observed between H- and P-GMSC lines. However, proliferation, cell size and osteogenic potential were higher in P-GMSCs, in contrast to their lower ability to suppress mononuclear cell proliferation. P. gingivalis up-regulated the mRNA expression of IL-6, IL-8, MCP-1, GRO-alpha, RANTES, TLR-2, HIF-1 alpha, OPG, MMP-3, SDF-1, HGF and IP-10 in P-GMSCs, whereas only IL-6, MCP-1 and GRO-alpha were up-regulated in H-GMSCs. The expression of MCP-1, RANTES, IP-10 and HGF was significantly higher in P-GMSCs compared to H-GMSCs, but IDO1 was lower. No significant changes in the expression of TLR-3, TLR-4, TGF-beta, LAP, IGFBP4 and TIMP-1 were observed in both types of GMSCs. In conclusion, our results suggest that P-GMSCs retain their pro-inflammatory properties in culture, exhibit lower immunosuppressive potential than their healthy counterparts, and impaired regeneration-associated gene induction in culture. All these functions are potentiated significantly by P. gingivalis treatment.",
publisher = "MDPI, Basel",
journal = "International Journal of Molecular Sciences",
title = "Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis",
number = "7",
volume = "23",
doi = "10.3390/ijms23073510"
}

Bekić, M., Radanović, M., Đokić, J., Tomić, S., Eraković, M., Radojević, D., Duka, M., Marković, D., Marković, M., Ismaili, B., Bokonjić, D.,& Čolić, M.. (2022). Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis. in International Journal of Molecular Sciences
MDPI, Basel., 23(7).
https://doi.org/10.3390/ijms23073510

Bekić M, Radanović M, Đokić J, Tomić S, Eraković M, Radojević D, Duka M, Marković D, Marković M, Ismaili B, Bokonjić D, Čolić M. Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis. in International Journal of Molecular Sciences. 2022;23(7).
doi:10.3390/ijms23073510 .

Bekić, Marina, Radanović, Marina, Đokić, Jelena, Tomić, Sergej, Eraković, Mile, Radojević, Dušan, Duka, Milos, Marković, Dejan, Marković, Milan, Ismaili, Bashkim, Bokonjić, Dejan, Čolić, Miodrag, "Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis" in International Journal of Molecular Sciences, 23, no. 7 (2022),
https://doi.org/10.3390/ijms23073510 . .