Linagliptin inhibits lipopolysaccharide-induced inflammation in human U937 monocytes

Abstract

BackgroundAtherosclerosis and inflammation are more common in patients with diabetes than in patients without diabetes, and atherosclerosis progression contributes to inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of patients with diabetes. Linagliptin is the only bile-excreted, anti-diabetic oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Although the anti-inflammatory effects of DPP-4 inhibitors in vivo and in vitro have been reported, few in vitro studies have examined the effects of linagliptin using monocytes, which play a central role in arteriosclerosis-related inflammation. Herein, we assessed the anti-inflammatory effects of linagliptin in human U937 monocytes.MethodsU937 cells at densities of 1 × 106 cells/mL were cultured in Roswell Park Memorial Institute medium supplied with 10% fetal bovine serum and treated with 100 nM phorbol myristate acetate for 48 h for differentiation into macrophages. The media were replaced, and the cells were pretreated with 1, 5, 10, 50, and 100 nM linagliptin for 1 h or were left untreated. The media were then replaced again, and the cells were treated with 1 μg/mL lipopolysaccharide (LPS) or 10 nM interleukin (IL)-1β only, in combination with 1, 5, 10, 50, and 100 nM linagliptin or were left untreated. The extracted media were used to measure IL-6 and tumor necrosis factor (TNF)-α levels using enzyme-linked immunosorbent assay kits.ResultsLPS alone significantly increased IL-6 and TNF-α production compared with the control treatment. The treatment of cells with linagliptin at all concentrations significantly inhibited the LPS-stimulated IL-6 and TNF-α production. Meanwhile, IL-1β alone significantly increased IL-6 production compared with the control treatment. No significant difference in IL-6 production was noted between the cells treated with IL-1β and simultaneous treatment with IL-1β and linagliptin.ConclusionsLinagliptin inhibited LPS-induced inflammation in human monocytic U937 cells.

<p>DPP-4 Inhibitor Linagliptin Ameliorates Oxidized LDL-Induced THP-1 Macrophage Foam Cell Formation and Inflammation</p>

“…Currently, we do not understand how the inhibition of DPP-4 in macrophages reduces the activity of these receptors and transporters. As mentioned before, Linagliptin shows the capacity to modulate macrophages toward M2 polarization, 14,22 but its action in the process of foam cell formation could be different. One feasible hypothesis is that DPP-4 agonists can be considered as a class of competitive inhibitors to determine whether the effect of Linagliptin is solely dependent on DPP-4 activity in foam cells.…”

“…23 The most recent study indicates that Linagliptin increases M2 macrophage polarization by inhibiting DPP-4 expression and activity. 14 Similarly, Alogliptin inhibits visceral adipose tissue macrophage content in atherosclerotic mice. 7 Vildagliptin suppresses macrophage foam cell formation in both non-diabetic and diabetic mice.…”

“…13 A most recent mouse model study has shown that Linagliptin exhibits a protective effect in high fat diet-induced atherosclerosis and promotes macrophages toward M2 polarization. 14 In in vitro experiments, Linagliptin exhibits an anti-inflammatory effect by inhibiting monocyte adhesion to vascular endothelial cells. 15 However, the underlying mechanism remains elusive.…”

Effect of a DPP‐4 Inhibitor on Orthodontic Tooth Movement and Associated Root Resorption

“…It has recently been identified as an important risk factor for osteoporosis-associated fractures [ 26 , 27 ], but the long-term use of some antidiabetic drugs was reported to have side effects for bone metabolism [ 28 , 29 ]. Indeed, a DPP-4 inhibitor was recently shown to have anti-inflammatory actions in several types of vascular cells and immune cells [ 30 , 31 ], while linagliptin has potent beneficial effects in some inflammatory diseases [ 8 , 32 ]. There are few reports regarding the outcome of short-term DPP-4 inhibitor administration, and this study is the first to report the effect of DPP-4 inhibition on OTM and associated root resorption.…”

Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases

“…Yamadera et al (2018) in their in vitro study demonstrated a reduction of LPS-induced (lipopolysaccharide) inflammation after linagliptin administration. The production of IL-6 and TNF-α by pro-inflammatory monocytes was significantly reduced in relation to the control sample [32]. Increased levels of IL-6 and TNF-α in both CSF (cerebrospinal fluid) and serum have been associated with deterioration of neurological functions, increased infarct size and poor functional outcome [16,33,34].…”