The proteolytic action of DPP4 is one of the multiple functions of the protein, with other functions including receptor activity, co-stimulatory functions, binding and interactions with various proteins, and a role in apoptosis. In line with its multiple functions, DPP4 is widely distributed in tissues and also present in serum as a soluble protein. DPP4 plays important roles in T cell functions, including activation, proliferation, migration, and memory response. Shirakawa et al. reported that M1 macrophages and CD8+ T cells were increased in the visceral adipose tissue of diet-induced diabetic mice and that DPP4 inhibition prevented the infiltration of those cells into VAT, suggesting that DPP4 may be involved in the development of adipose tissue inflammation in this animal model. DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. We assessed a role of DPP4 in macrophage (Mac)- mediated inflammation in relation to insulin resistance. We stimulated mouse bone marrow-derived Mac (BMDM) or RAW 264.7 cells, with LPS or palmitic acid (PA) and assessed anti-inflammatory action of DPP4 inhibitor. We confirmed DPP4 expression and its enzymatic activity in RAW 264.7 cells. Vildagliptin suppressed the increase in nitric oxide (NO) secretion from LPS- or PA-stimulated RAW264.7 cells. In addition, Vildagliptin significantly suppressed the secretion of cytokines from PA-stimulated mouse BMDM. In the inflammatory conditioned-RAW264.7 cells and 3T3-L1 adipocytes, Vildagliptin had a marked suppressing effect on JNK activation among various molecular pathways. These findings suggest a role of DPP4 in the inflammatory reaction mediated by Mac and a new clinical relevance of DPP4 inhibition. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Various DPP4 substrates seem to be involved in these non-glycemic actions of DPP4 inhibitors.