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Exenatide and metformin express their anti-inflammatory effects on human monocytes/macrophages by the attenuation of MAPKs and NFκB signaling

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Abstract

Metformin and exenatide are effective antidiabetic drugs, and they seem to have pleiotropic properties improving cardiovascular outcomes. Macrophages’ phenotype is essential in the development of atherosclerosis, and it can be modified during antidiabetic therapy, resulting in attenuated atherogenesis. The mechanism orchestrating this phenomenon is not fully clear. We examined the impact of exenatide and metformin on the level of TNF alpha, MCP-1, reactive oxygen species (ROS), and the activation of mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NFκB), and CCAAT/enhancer-binding protein beta (C/EBP beta) in human monocytes/macrophages. We found that both drugs reduced levels of TNF alpha, ROS, and NFκB binding activity to a similar extent. Compared to metformin, exenatide was more effective in reducing MCP-1 levels. We noted that Compound C (AMPK inhibitor) reduced the impact of exenatide on cytokines, ROS, and NFκB in cultures. Both drugs elevated the C/EBP beta phosphorylation level. Experiments on MAPKs showed effective inhibitory potential of exenatide toward p38, JNK, and ERK, whereas metformin inhibited JNK and ERK only. Exenatide was more effective in the inhibition of JNK than metformin. Interestingly, an in vitro setting additive effect of drugs was absent. In conclusion, here, we report that metformin and exenatide inhibit the proinflammatory phenotype of human monocytes/macrophages via influence on MAPK, C/EBP beta, and NFκB. Exenatide was more effective than metformin in reducing MCP-1 expression and JNK activity. We also showed that some effects of exenatide relied on AMPK activation. This shed light on the possible mechanisms responsible for pleiotropic effects of metformin and exenatide.

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References

  • Aiello RJ, Bourassa PA, Lindsey S, Weng W, Natoli E, Rollins BJ, et al. (1999) Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 19(6):1518–1525

    Article  CAS  PubMed  Google Scholar 

  • Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, et al. (2010) Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59(4):1030–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Batchuluun B, Inoguchi T, Sonoda N, Sasaki S, Inoue T, Fujimura Y, et al. (2014) Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis 232(1):156–164

    Article  CAS  PubMed  Google Scholar 

  • Ben-Shlomo S, Zvibel I, Shnell M, Shlomai A, Chepurko E, Halpern Z, et al. (2011) Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol 54(6):1214–1223

    Article  CAS  PubMed  Google Scholar 

  • Bułdak Ł, Łabuzek K, Bułdak RJ, Kozłowski M, Machnik G, Liber S, et al. (2014) Metformin affects macrophages’ phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep 66(3):418–429

    Article  PubMed  Google Scholar 

  • Bułdak Ł, Łabuzek K, Bułdak RJ, Machnik G, Bołdys A, Okopień B (2015) Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages. Naunyn Schmiedeberg’s Arch Pharmacol 388(9):905–919

    Article  Google Scholar 

  • Bułdak Ł, Łabuzek K, Bułdak R, Machnik G, Bołdys A, Basiak M, et al. (2016a) Metformin reduces the expression of NADPH oxidase and increases the expression of antioxidative enzymes in human monocytes/macrophages cultured in vitro. Exp Ther Med 11(3):1095–1103

    PubMed  PubMed Central  Google Scholar 

  • Bułdak Ł, Machnik G, Bułdak RJ, Łabuzek K, Bołdys A, Belowski D, et al. (2016b) Exenatide (a GLP-1 agonist) expresses anti-inflammatory properties in cultured human monocytes/macrophages in a protein kinase A and B/Akt manner. Pharmacol Rep 68(2):329–337

    Article  PubMed  Google Scholar 

  • Bryk D, Olejarz W, Zapolska-Downar D (2014) Mitogen-activated protein kinases in atherosclerosis. Postȩpy Hig Med Dośw 68:10–22

    Article  Google Scholar 

  • Cheang WS, Tian XY, Wong WT, Lau CW, Lee SS, Chen ZY, Yao X, Wang N, Huang Y (2014) Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5’ adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor δ pathway. Arterioscler Thromb Vasc Biol 34(4):830–836

    Article  CAS  PubMed  Google Scholar 

  • Cominacini L, Anselmi M, Garbin U, Fratta Pasini A, Stranieri C, Fusaro M, et al. (2005) Enhanced plasma levels of oxidized low-density lipoprotein increase circulating nuclear factor-kappa B activation in patients with unstable angina. J Am Coll Cardiol 46(5):799–806

    Article  CAS  PubMed  Google Scholar 

  • Cho YM, Kieffer TJ (2011) New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 54(2):219–222

    Article  CAS  PubMed  Google Scholar 

  • Dai Y-L, Huang S-L, Leng Y (2015) AICAR and metformin exert AMPK-dependent effects on INS-1E pancreatic β-cell apoptosis via differential downstream mechanisms. Int J Biol Sci 11(11):1272–1280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Epstein FH, Barnes PJ, Karin M (1997) Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336(15):1066–1071

    Article  Google Scholar 

  • Erdogdu O, Eriksson L, Xu H, Sjöholm A, Zhang Q, Nyström T (2013) Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol 50(2):229–241

    Article  CAS  PubMed  Google Scholar 

  • Fisk M, Gajendragadkar PR, Mäki-Petäjä KM, Wilkinson IB, Cheriyan J (2014) Therapeutic potential of p38 MAP kinase inhibition in the management of cardiovascular disease. Am J Cardiovasc Drugs Drugs Devices Interv 14(3):155–165

    Article  CAS  Google Scholar 

  • Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci 24(2):479–487

    Article  CAS  PubMed  Google Scholar 

  • Gou S, Zhu T, Wang W, Xiao M, Wang X, Chen Z (2014) Glucagon like peptide-1 attenuates bleomycin-induced pulmonary fibrosis, involving the inactivation of NF-κB in mice. Int Immunopharmacol 22(2):498–504

    Article  PubMed  Google Scholar 

  • Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, et al. (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2(2):275–281

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa K, Wang X, Lo EH (2016) CD200 increases alternatively activated macrophages through cAMP-response element binding protein - C/EBP-beta signaling. J Neurochem 136(5):900–906

    Article  CAS  PubMed  Google Scholar 

  • He L, Wong CK, Cheung KK, Yau HC, Fu A, Zhao H-L, et al. (2013) Anti-inflammatory effects of exendin-4, a glucagon-like peptide-1 analog, on human peripheral lymphocytes in patients with type 2 diabetes. J Diabetes Investig 4(4):382–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu C-C, Lien J-C, Chang C-W, Chang C-H, Kuo S-C, Huang T-F (2013) Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation. Biochem Pharmacol 85(3):385–395

    Article  CAS  PubMed  Google Scholar 

  • Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. (2006) Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26(3):611–617

    Article  CAS  PubMed  Google Scholar 

  • Khazen W, M’bika J-P, Tomkiewicz C, Benelli C, Chany C, Achour A, et al. (2005) Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Lett 579(25):5631–5634

    Article  CAS  PubMed  Google Scholar 

  • Klein J, Westphal S, Kraus D, Meier B, Perwitz N, Ott V, et al. (2004) Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes. J Endocrinol 183(2):299–307

    Article  CAS  PubMed  Google Scholar 

  • Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, et al. (2011) Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 54(4):965–978

    Article  CAS  PubMed  Google Scholar 

  • Koeners MP, Wesseling S, Sánchez M, Braam B, Joles JA (2016) Perinatal inhibition of NF-kappaB has long-term antihypertensive and renoprotective effects in fawn-hooded hypertensive rats. Am J Hypertens 29(1):123–131

    Article  PubMed  Google Scholar 

  • Krasner NM, Ido Y, Ruderman NB, Cacicedo JM (2014) Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One 9(5):e97554

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Z, Ni C-L, Yao Z, Chen L-M, Niu W-Y (2014) Liraglutide enhances glucose transporter 4 translocation via regulation of AMP-activated protein kinase signaling pathways in mouse skeletal muscle cells. Metabolism 63(8):1022–1030

    Article  CAS  PubMed  Google Scholar 

  • Mamputu JC, Wiernsperger NF, Renier G (2003) Antiatherogenic properties of metformin: the experimental evidence. Diabetes Metab 29(4 Pt 2):6S71–6S76

    CAS  PubMed  Google Scholar 

  • Navab M, Fogelman AM, Berliner JA, Territo MC, Demer LL, Frank JS, et al. (1995) Pathogenesis of atherosclerosis. Am J Cardiol 76(9):18C–23C

    Article  CAS  PubMed  Google Scholar 

  • Okopień B, Kowalski J, Krysiak R, Łabuzek K, Stachura-Kułach A, Kułach A, et al. (2005) Monocyte suppressing action of fenofibrate. Pharmacol Rep Prog 57(3):367–372

    Google Scholar 

  • Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22(2):153–183

    CAS  PubMed  Google Scholar 

  • Porras A, Alvarez AM, Valladares A, Benito M (1998) p42/p44 mitogen-activated protein kinases activation is required for the insulin-like growth factor-I/insulin induced proliferation, but inhibits differentiation, in rat fetal brown adipocytes. Mol Endocrinol Baltim Md 12(6):825–834

    Article  CAS  Google Scholar 

  • Rosenstock J, Raccah D, Korányi L, Maffei L, Boka G, Miossec P, et al. (2013) Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 36(10):2945–2951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh R, Devi S, Gollen R (2015) Role of free radical in atherosclerosis, diabetes and dyslipidaemia: larger-than-life. Diabetes Metab Res Rev 31(2):113–126

    Article  CAS  PubMed  Google Scholar 

  • Spychalowicz A, Wilk G, Śliwa T, Ludew D, Guzik TJ (2012) Novel therapeutic approaches in limiting oxidative stress and inflammation. Curr Pharm Biotechnol 13(13):2456–2466

    Article  CAS  PubMed  Google Scholar 

  • Tang S-T, Zhang Q, Tang H-Q, Wang C-J, Su H, Zhou Q, et al 2016 Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways. Endocrine

  • Tsukada J, Yoshida Y, Kominato Y, Auron PE (2011) The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine 54(1):6–19

    Article  CAS  PubMed  Google Scholar 

  • UK Prospective Diabetes Study (UKPDS) Group (1998a) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352(9131):854–865

    Article  Google Scholar 

  • Victor VM, Rovira-Llopis S, Bañuls C, Diaz-Morales N, Lopez-Domenech S, Escribano-López I, et al. (2015) Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients. Atherosclerosis 242(1):167–173

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Sun Y, Lin P, Song J, Zhao R, Li W, et al. (2015) Liraglutide activates AMPK signaling and partially restores normal circadian rhythm and insulin secretion in pancreatic islets in diabetic mice. Biol Pharm Bull 38(8):1142–1149

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Parlevliet ET, Geerling JJ, van der Tuin SJL, Zhang H, Bieghs V, et al. (2014) Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. Br J Pharmacol 171(3):723–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia M, Sui Z (2009) Recent developments in CCR2 antagonists. Expert Opin Ther Pat 19(3):295–303

    Article  CAS  PubMed  Google Scholar 

  • Xu W-W, Guan M-P, Zheng Z-J, Gao F, Zeng Y-M, Qin Y, et al. (2014) Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway. Cell Physiol Biochem 33(2):423–432

    Article  CAS  PubMed  Google Scholar 

  • Yang C-S, Kim J-J, Lee H-M, Jin HS, Lee S-H, Park J-H, et al. (2014) The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy. Autophagy 10(5):785–802

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, He X, Chen Y, Huang Y, Wu L, He J (2015) Exendin-4 attenuates cardiac hypertrophy via AMPK/mTOR signaling pathway activation. Biochem Biophys Res Commun 468(1–2):394–399

    Article  CAS  PubMed  Google Scholar 

  • Zwergal A, Quirling M, Saugel B, Huth KC, Sydlik C, Poli V, et al. (2006) C/EBP blocks p65 phosphorylation and thereby NF- B-mediated transcription in TNF-tolerant cells. J Immunol 177(1):665–672

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to Mrs. Jaroslawa Sprada and Mrs. Halina Klimas for their excellent technical support.

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Authors and Affiliations

  1. Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Medykow 18, 40-752, Katowice, Poland

    Łukasz Bułdak, Grzegorz Machnik, Krzysztof Łabuzek, Aleksandra Bołdys & Bogusław Okopień

  2. Department of Physiology, School of Medicine in Zabrze, Medical University of Silesia, Jordana 19, 41-808, Zabrze, Poland

    Rafał Jakub Bułdak

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  1. Łukasz Bułdak
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  2. Grzegorz Machnik
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  3. Rafał Jakub Bułdak
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  4. Krzysztof Łabuzek
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  5. Aleksandra Bołdys
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  6. Bogusław Okopień
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Correspondence to Łukasz Bułdak.

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Volunteers who were recruited from the Department of Internal Medicine and Clinical Pharmacology (Medical University of Silesia, Katowice, Poland) gave written informed consent to participate in the study protocol. The ethical committee of the Medical University of Silesia approved the study protocol.

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The authors declare that they have no conflicts of interest.

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The study was supported by a statutory grant from the Medical University of Silesia (Grant No. KNW-1-093/N/5/0).

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Bułdak, Ł., Machnik, G., Bułdak, R.J. et al. Exenatide and metformin express their anti-inflammatory effects on human monocytes/macrophages by the attenuation of MAPKs and NFκB signaling. Naunyn-Schmiedeberg's Arch Pharmacol 389, 1103–1115 (2016). https://doi.org/10.1007/s00210-016-1277-8

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  • DOI: https://doi.org/10.1007/s00210-016-1277-8

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