Journal
ATHEROSCLEROSIS
Volume 213, Issue 2, Pages 429-435Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2010.08.064
Keywords
Dipeptidyl peptidase-4; CD26; Mitogen-activated protein kinase; Matrix metalloproteinase; Atherosclerosis
Funding
- Takeda Pharmaceuticals North America, Inc.
- Department of Veterans Affairs
- NIH [DE016353]
Ask authors/readers for more resources
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. Published by Elsevier Ireland Ltd.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available