Sitagliptin (MK0431) inhibition of dipeptidyl peptidase IV decreases nonobese diabetic mouse CD4+ T-cell migration through incretin-dependent and -independent pathways

Abstract

OBJECTIVE - Treatment of NOD mice with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin preserved islet transplants through a pathway involving modulation of splenic CD4+ T-cell migration. In the current study, effects of sitagliptin on migration of additional subsets of CD4+ T-cells were examined and underlying molecular mechanisms were further defined. RESEARCH DESIGN AND METHODS - Effects of sitagliptin on migration of NOD mouse splenic, thymic, and lymph node CD4+ T-cells were determined. Signaling modules involved in DPP-IV-, Sitagliptin- and incretin-mediated modulation of CD4+ T-cell migration were studied using Western blot and Rac1 and nuclear factor-κB (NF-κB) activity assays. RESULTS - Migration of splenic and lymph node CD4+ T-cells of diabetic NOD mice was reduced by sitagliptin treatment. In vitro treatment of splenic, but not thymic or lymph node CD4+ T-cells, from nondiabetic NOD mice with soluble (s) DPP-IV increased migration. Sitagliptin abolished sDPP-IV effects on splenic CD4+ T-cell migration, whereas incretins decreased migration of lymph node, but not splenic, CD4+ T-cells. Splenic CD4 + T-cells demonstrating increased in vitro migration in response to sDPP-IV and lymph node CD4+ T-cells that were nonresponsive to incretins selectively infiltrated islets of NOD mice, after injection. Sitagliptin decreases migration of splenic CD4+ T-cells through a pathway involving Rac1/vasodilator-stimulated phosphoprotein, whereas its inhibitory effects on the migration of lymph node CD4+ T-cells involve incretin-activation of the NF-κB pathway. CONCLUSIONS - Benefits of sitagliptin treatment in diabetic NOD mice may be mediated through selective effects on subpopulations of T-cells that are related to autoimmunity. © 2010 by the American Diabetes Association.