4.5 Article

DPP-4 Inhibitors Repress NLRP3 Inflammasome and Interleukin-1beta via GLP-1 Receptor in Macrophages Through Protein Kinase C Pathway

期刊

CARDIOVASCULAR DRUGS AND THERAPY
卷 28, 期 5, 页码 425-432

出版社

SPRINGER
DOI: 10.1007/s10557-014-6539-4

关键词

DPP-4; Inflammation; GLP-1; PKC

资金

  1. national natural science foundation for fostering young scholars of china [2013KJ25]
  2. department of veterans affairs, veterans health administration, office of research and development, biomedical laboratory research and development, Washington, DC

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Anti-atherosclerotic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown in many studies. Since inflammation and immune response play a key role in atherogenesis, we examined the effect of DPP-4 inhibitors on the expression of nod-like receptor family, pyrin domain containing 3 (NLRP3) Inflammasome and Interleukin-1beta (IL-1 beta) in human macrophages. THP-1 macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with or without DPP-4 inhibitors (sitagliptin and NVPDPP728). The effects of DPP-4 inhibitors on the expression of NLRP3, toll-like receptor 4 (TLR4) and pro-inflammatory cytokine IL-1 beta were studied. Both DPP-4 inhibitors induced a significant reduction in NLRP3, TLR4 and IL-1 beta expression; concurrently, there was an increase in glucagon like peptide 1 receptor (GLP-1R) expression. Simultaneously, DPP-4 inhibitors reduced phosphorylated-PKC, but not PKA, levels. To determine the role of PKC activation in the effects of DPP-4 inhibitors, cells were treated with PMA- which blocked the effect of DPP-4 inhibitors on NLRP3 and IL-1 beta as well as TLR4 and GLP-1R. Over-expression of GLP-1R in macrophages with its agonist liraglutide also blocked the effects of PMA. DPP-4 inhibitors suppress NLRP3, TLR4 and IL-1 beta in human macrophages through inhibition of PKC activity. This study provides novel insights into the mechanism of inhibition of inflammatory state and immune response in atherosclerosis by DPP-4 inhibitors.

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