DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes

Abstract Dipeptidyl peptidase-4 (DPP-4)/CD26, a cell surface glycoprotein, is expressed by a variety of cells including T cells, B cells, NK cells, and macrophages. Although it has been shown that DPP-4/CD26 is involved in T cell activation, its role in biological functions in macrophages has not be...

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Published in:Atherosclerosis 2010-12, Vol.213 (2), p.429-435
Main Authors: Ta, Nga N, Li, Yanchun, Schuyler, Corinne A, Lopes-Virella, Maria F, Huang, Yan
Format: Article
Language:English
Subjects:
Arterial hypertension. Arterial hypotension
Atherosclerosis
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Cardiovascular
CD26
Clinical manifestations. Epidemiology. Investigative techniques. Etiology
Dipeptidyl Peptidase 4 - physiology
Dipeptidyl peptidase-4
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Extracellular Signal-Regulated MAP Kinases - metabolism
Flavonoids - pharmacology
Humans
Lipopolysaccharides - pharmacology
Macrophages - drug effects
Macrophages - physiology
Matrix metalloproteinase
Matrix Metalloproteinase 1 - biosynthesis
Matrix Metalloproteinase Inhibitors
Medical sciences
Mitogen-activated protein kinase
Piperidines - pharmacology
Toll-Like Receptor 4 - metabolism
U937 Cells
Uracil - analogs & derivatives
Uracil - pharmacology
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Summary:Abstract Dipeptidyl peptidase-4 (DPP-4)/CD26, a cell surface glycoprotein, is expressed by a variety of cells including T cells, B cells, NK cells, and macrophages. Although it has been shown that DPP-4/CD26 is involved in T cell activation, its role in biological functions in macrophages has not been well investigated. In this study, we used alogliptin, a specific inhibitor of DPP 4/CD26, to study the effect of DPP-4/CD26 on the activation of the extracellular signal-regulated kinase (ERK) that plays a critical role in the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs) in U937 histiocytes. Results showed that 1 nM of alogliptin inhibited ERK phosphorylation induced by lipopolysaccharide (LPS), a ligand for toll-like receptor (TLR)4, by 91%. Furthermore, results showed that alogliptin inhibited LPS-stimulated MMP-1 expression in a concentration-dependent manner and 1 nM of alogliptin inhibited MMP-1 expression by 60%. To confirm the involvement of the ERK pathway in MMP-1 expression by U937 cells, we showed that PD98059, a specific inhibitor for the ERK pathway, blocked LPS-stimulated MMP-1 expression. In addition to MMP-1, our study showed that alogliptin also inhibited MMP-9, -12 and -15, but had no effect on TIMP-1 and -2 expression. Taken together, this study showed for the first time that the inhibition of DPP-4/CD26 by alogliptin suppressed TLR4-mediated ERK activation and ERK-dependent MMP expression by U937 cells, suggesting that DPP-4/CD26 may play an important role in macrophage-mediated inflammation response and tissue remodeling.
ISSN:0021-9150
1879-1484
DOI:10.1016/j.atherosclerosis.2010.08.064