Sitagliptin Induces Tolerogenic Human Dendritic Cells

Area of Science:

• Immunology
• Endocrinology
• Cell Biology

Background:

• Sitagliptin is an anti-diabetic medication that inhibits dipeptidyl peptidase (DPP)-4/CD26.
• Sitagliptin possesses anti-inflammatory and immunomodulatory properties beyond its glucose-lowering effects.

Purpose of the Study:

• To investigate the impact of sitagliptin on the differentiation and function of human monocyte-derived dendritic cells (MoDCs).
• To explore the potential of sitagliptin-induced MoDCs in managing autoimmune diseases and allotransplant rejection.

Main Methods:

• Human MoDCs were generated and matured with or without sitagliptin at different time points (0d and 4d).
• MoDC differentiation and maturation were assessed by surface marker expression (CD40, CD83, CD86, CD14, CD26, HLA-DR) and cytokine production (IL-1β, IL-12p70, IL-23, IL-27, IL-10, TGF-β).
• T-cell alloproliferative responses, T-helper cell polarization, and regulatory T-cell (Treg) induction were evaluated in co-culture systems. Western blot analysis was used to examine NF-κB and p38MAPK signaling pathways.

Main Results:

• Sitagliptin impaired MoDC differentiation and maturation, reducing co-stimulatory molecule and inflammatory cytokine expression while increasing tolerogenic markers (CD26, ILT4, IDO1) and immunoregulatory cytokines (IL-10, TGF-β).
• Sitagliptin-treated MoDCs exhibited reduced allostimulatory capacity, suppressed Th1/Th17 responses, and augmented Th2/Treg responses.
• Sitagliptin treatment increased the frequency of Tregs (including Tr1 cells) and modulated NF-κB and p38MAPK signaling pathways.

Conclusions:

• Sitagliptin induces the differentiation of tolerogenic dendritic cells.
• The immunomodulatory effects of sitagliptin on DCs suggest its therapeutic potential for autoimmune diseases and prevention of transplant rejection.