Journal of Pharmaceutics & Drug Delivery Research

Sitagliptin Inhibits the Lipopolysaccharide-Induced Inflammation

Hitomi Hasegawa, Yuya Nakamura, Mayumi Tsuji, Ran Ono, Tatsunori Oguchi, Katsuji Oguchi, Yuji Kiuchi, Isao Ohsawa, Hiromichi Gotoh, Yoshikazu Goto and Masahiro Inagaki

Sitagliptin Inhibits the Lipopolysaccharide-Induced Inflammation

Abstract

Objective: Sitagliptin is an anti-diabetic Dipeptidyl peptidase-4 (DPP-4) inhibitor; used worldwide with a well-established evidence base as an effective anti-diabetic therapy and the lowest cost of all DPP-4 inhibitors. Atherosclerosis and inflammation are more common in diabetic patients than in nondiabetic patients, and progression of atherosclerosis contributes to this inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of diabetic patients. Although several reports have investigated the anti-inflammatory mechanisms of sitagliptin in vitro, none of these studies has described its effects on mitogenactivated protein kinase (MAPK) in human umbilical vein endothelial cells (HUVECs) stimulated with lipopolysaccharide (LPS). We assessed the MAPK-dependent anti-inflammatory effects of sitagliptin in HUVECs.

Methods: HUVECs (1–2 × 105 cell/mL) were either pretreated with different doses of sitagliptin for 1 h or left untreated. Subsequently, HUVECs were either incubated with lipopolysaccharide (LPS) together with sitagliptin (after treatment) or left untreated. Five hours post incubation, the culture medium was sampled for interleukin (IL)-6. Additionally, intranuclear p65 levels were measured 5 h after simultaneous treatment with LPS and sitagliptin. p38 MAPK levels and PKC activity were measured in the cytosolic fractions 30 min after simultaneous treatment with LPS and sitagliptin.

Results: Treatment with LPS alone induced significant IL-6 production compared with untreated control cells. Pretreatment of cells with sitagliptin at all concentrations tested significantly reduced LPS-stimulated IL-6 production. However, after treatment of cells with sitagliptin at any concentration did not inhibit LPS-stimulated IL-6 production. Compared to untreated cells, treatment with 5 nM sitagliptin significantly inhibited LPS-stimulated intranuclear p65 expression, and p38 MAPK phosphorylation. There was no significant difference in PKC activity with LPS or sitagliptin.

Conclusion: In HUVECs, sitagliptin elicits its anti-inflammatory effects through MAPK-dependent mechanisms.