Abstract 92: A Novel Role for Dipeptidyl Peptidase-4 and Adenosine Deaminase in Regulating Macrophage and Dendritic Cell Function: Implications for Treatment of Type 2 Diabetes
Introduction: In addition to its powerful effects on glycemic control via enzymatic degradation of incretins, Dipeptidyl peptidase-4 (DDP4) also exerts non-metabolic functions. Despite the ubiquitous use of DPP4 inhibitors in the treatment of Type 2 diabetes (T2D), their effects on immune cell function are poorly understood.
Hypothesis: In this study, we investigated the hypothesis that DPP4 may play a critical role in modulating T cell proliferation through its expression on dendritic cells (DCs) and further characterized its role in adipose inflammation in patients with morbid obesity.
Methods: Monocytes were isolated from peripheral blood of healthy donors. DCs were induced from monocytes by rhGM-CSF and rhIL-4. DPP4 expression and T-cell proliferation were detected by flow cytometry. DPP4 knockdown was accomplished by transient transfection with DPP4-specific siRNA. Human visceral adipose tissues were used for stromal vascular fraction isolation.
Results: 7.5±3.1% (n=10) of peripheral monocytes expressed DPP4. DPP4 dramatically increased when monocyte was differentiated to DC/Macrophage or activated by LPS. Interestingly, DPP4 expression was much higher on the DC/Macrophage in adipose tissue than that of peripheral blood. Furthermore, an increase of DPP4 on adipose tissue macrophages in obese patients was observed (13.2±2.4 vs. 7.9±1.6 for obese vs. lean, n=5). And there was a correlation between DPP4 expression and insulin level (y = 0.9094x-3.6088, R2=0.6943). Cell surface DPP4 was able to bind adenosine deaminase (ADA). The binding enhanced the capability of DCs to stimulate T-cell proliferation by relieving the suppressive effect of adenosine on T-cell proliferation. Knockdown of DPP4 on DCs by siRNA attenuated their ability to stimulate T-cell proliferation without influence on the secretion of pro-inflammatory cytokines by DCs.
Conclusions: DPP4 on DCs mediates binding of ADA and may re-create a microenvironment suitable for T-cell proliferation. This interaction in DCs between ADA and DPP4 may promote adipose T-cell inflammation and play facilatatory role in T2D. Pro-inflammatory effects of DPP4 and the elucidation of its enzymatic v.s. non-enzymatic contributions may be of fundamental importance in the understanding of T2D.
- © 2012 by American Heart Association, Inc.