title: Exenatide (a GLP-1 agonist) expresses anti-inflammatory properties in cultured human monocytes/macrophages in a protein kinase A and B/Akt manner.
abstract: BACKGROUND
  Incretin-based therapies in the treatment of type 2 diabetes mellitus are associated with significant improvements in glycemic control, which are accompanied by a beneficial impact on atherosclerosis. Macrophages are essential in the development of atherosclerotic plaques and may develop features that accelerate atherosclerosis (classically activated macrophages) or protect arterial walls against it (alternatively activated macrophages). Therefore, we explored whether beneficial actions of exenatide are connected with the influence on the macrophages' phenotype and synthesis of inflammatory and anti-inflammatory cytokines.
  
  
  METHODS
  Monocytes/macrophages were harvested from 10 healthy subjects. Cells were cultured in the presence of exenatide, exendin 9-39 (GLP-1 antagonist), LPS, IL-4, PKI (PKA inhibitor) and triciribine (PKB/Akt inhibitor). We measured the effects of the above-mentioned compounds on markers of macrophages' phenotype (inducible nitrous oxide (iNOS), arginase 1 (arg1) and mannose receptors) and concentration of nitrite, IL-1β, TNF-α and IL-10.
  
  
  RESULTS
  Exenatide significantly increased the level of IL-10 and decreased both TNF-α and IL-1β in LPS-treated monocytes/macrophages. Furthermore exenatide increased the expression of arg1-a marker of classical activation and reduced the LPS-induced expression of iNOS-a marker of classical activation. According to experiments with protein kinases inhibitors we found that proinflammatory markers were protein kinase A dependent, whereas the activation of alternative activation was similarly reliant on protein kinase A and B/Akt.
  
  
  CONCLUSIONS
  We showed that exenatide skewed the macrophages phenotype toward anti-inflammatory phenotype and this effect is predominantly attributable to protein kinase A and to a less extent to B/Akt activation.
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. Electronic address: lbuldak@gmail.com.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Bułdak
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Machnik
authors.affiliation: Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Zabrze, Poland.
authors.forename: Rafał Jakub
authors.initials: RJ
authors.lastname: Bułdak
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Łabuzek
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bołdys
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Belowski
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Basiak
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors.forename: Bogusław
authors.initials: B
authors.lastname: Okopień
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; D016753:Interleukin-10; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Atherosclerosis; Diabetes; Exenatide; Inflammation; Macrophage