title: DPP-4 inhibitors repress NLRP3 inflammasome and interleukin-1beta via GLP-1 receptor in macrophages through protein kinase C pathway.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Division, Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR, 72212, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Dai
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D018929:Cell Culture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D058847:Inflammasomes / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D000069450:Liraglutide; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011719:Pyrazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000068900:Sitagliptin Phosphate; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D014230:Triazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D002352:Carrier Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009570:Nitriles; D011719:Pyrazines; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D051197:Toll-Like Receptor 4; D014230:Triazoles; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D000068900:Sitagliptin Phosphate