PMID- 26922535 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20220316 IS - 2299-5684 (Electronic) IS - 1734-1140 (Linking) VI - 68 IP - 2 DP - 2016 Apr TI - Exenatide (a GLP-1 agonist) expresses anti-inflammatory properties in cultured human monocytes/macrophages in a protein kinase A and B/Akt manner. PG - 329-37 LID - S1734-1140(15)00345-X [pii] LID - 10.1016/j.pharep.2015.10.008 [doi] AB - 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-1beta, TNF-alpha and IL-10. RESULTS: Exenatide significantly increased the level of IL-10 and decreased both TNF-alpha and IL-1beta 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. CI - Copyright (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. FAU - Buldak, Lukasz AU - Buldak L AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. Electronic address: lbuldak@gmail.com. FAU - Machnik, Grzegorz AU - Machnik G AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. FAU - Buldak, Rafal Jakub AU - Buldak RJ AD - Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Zabrze, Poland. FAU - Labuzek, Krzysztof AU - Labuzek K AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. FAU - Boldys, Aleksandra AU - Boldys A AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. FAU - Belowski, Dariusz AU - Belowski D AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. FAU - Basiak, Marcin AU - Basiak M AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. FAU - Okopien, Boguslaw AU - Okopien B AD - Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151106 PL - Switzerland TA - Pharmacol Rep JT - Pharmacological reports : PR JID - 101234999 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (Peptides) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Venoms) RN - 130068-27-8 (Interleukin-10) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM EIN - Pharmacol Rep. 2017 Apr;69(2):376. PMID: 28179083 EIN - Pharmacol Rep. 2019 Oct;71(5):985-986. PMID: 31257077 MH - Anti-Inflammatory Agents/*pharmacology MH - Cells, Cultured MH - Cyclic AMP-Dependent Protein Kinases/*metabolism MH - Diabetes Mellitus, Type 2/metabolism MH - Exenatide MH - Glucagon-Like Peptide 1/*agonists MH - Humans MH - Inflammation/drug therapy/metabolism MH - Interleukin-10/metabolism MH - Interleukin-1beta/metabolism MH - Lipopolysaccharides/pharmacology MH - Macrophages/*drug effects/metabolism MH - Monocytes/*drug effects/metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Peptides/*pharmacology MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - Venoms/*pharmacology OTO - NOTNLM OT - Atherosclerosis OT - Diabetes OT - Exenatide OT - Inflammation OT - Macrophage EDAT- 2016/02/29 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/02/29 06:00 PHST- 2015/08/31 00:00 [received] PHST- 2015/10/21 00:00 [revised] PHST- 2015/10/22 00:00 [accepted] PHST- 2016/02/29 06:00 [entrez] PHST- 2016/02/29 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S1734-1140(15)00345-X [pii] AID - 10.1016/j.pharep.2015.10.008 [doi] PST - ppublish SO - Pharmacol Rep. 2016 Apr;68(2):329-37. doi: 10.1016/j.pharep.2015.10.008. Epub 2015 Nov 6.