DPP-4 inhibitors repress NLRP3 inflammasome and interleukin-1beta via GLP-1 receptor in macrophages through protein kinase C pathway

Cardiovasc Drugs Ther. 2014 Oct;28(5):425-32. doi: 10.1007/s10557-014-6539-4.

Abstract

Background: 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-1β) in human macrophages.

Methods and results: 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-1β were studied. Both DPP-4 inhibitors induced a significant reduction in NLRP3, TLR4 and IL-1β 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-1β as well as TLR4 and GLP-1R. Over-expression of GLP-1R in macrophages with its agonist liraglutide also blocked the effects of PMA.

Conclusion: DPP-4 inhibitors suppress NLRP3, TLR4 and IL-1β 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carrier Proteins / biosynthesis
  • Carrier Proteins / metabolism*
  • Cell Culture Techniques
  • Cyclic AMP-Dependent Protein Kinases / biosynthesis
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Inflammasomes / biosynthesis*
  • Interleukin-1beta / biosynthesis*
  • Liraglutide
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nitriles / antagonists & inhibitors
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinase C / metabolism*
  • Pyrazines / antagonists & inhibitors
  • Pyrazines / pharmacology
  • Pyrrolidines / antagonists & inhibitors
  • Pyrrolidines / pharmacology
  • Receptors, Glucagon / biosynthesis
  • Receptors, Glucagon / metabolism*
  • Signal Transduction / drug effects
  • Sitagliptin Phosphate
  • Tetradecanoylphorbol Acetate / analogs & derivatives
  • Tetradecanoylphorbol Acetate / pharmacology
  • Toll-Like Receptor 4 / biosynthesis
  • Triazoles / antagonists & inhibitors
  • Triazoles / pharmacology

Substances

  • 1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine
  • Carrier Proteins
  • Dipeptidyl-Peptidase IV Inhibitors
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nitriles
  • Pyrazines
  • Pyrrolidines
  • Receptors, Glucagon
  • Toll-Like Receptor 4
  • Triazoles
  • 4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate
  • Sitagliptin Phosphate