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

Reference69 articles.

1. A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide;Glenner;Histochemie,1966

2. CD26: A multi-purpose pharmacological target;Vincenzo;Curr. Clin. Pharmacol.,2014

3. CD26: An expanding role in immune regulation and cancer;Dang;Histol. Histopathol.,2002

4. Cut to the chase: A review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system;Klemann;Clin. Exp. Immunol.,2016

5. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins;Wagner;Clin. Exp. Immunol.,2016

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3