title: 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 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 1nM 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 1nM 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.
authors.affiliation: Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, United States.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Ta
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Li
authors.forename: Corinne A
authors.initials: CA
authors.lastname: Schuyler
authors.forename: Maria F
authors.initials: MF
authors.lastname: Lopes-Virella
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D020298:U937 Cells; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D005419:Flavonoids; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines; D051197:Toll-Like Receptor 4; D014498:Uracil; D048049:Extracellular Signal-Regulated MAP Kinases; D018819:Dipeptidyl Peptidase 4; D020781:Matrix Metalloproteinase 1; C520853:alogliptin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one