Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2015 Jul 9

PMID 26152715

Citations 159

Authors

Beth Kelly

Gillian M Tannahill

Michael P Murphy

Luke A J ONeill

Affiliations

Soon will be listed here.

Abstract

Metformin, a frontline treatment for type II diabetes mellitus, decreases production of the pro-form of the inflammatory cytokine IL-1β in response to LPS in macrophages. We found that it specifically inhibited pro-IL-1β production, having no effect on TNF-α. Furthermore, metformin boosted induction of the anti-inflammatory cytokine IL-10 in response to LPS. We ruled out a role for AMP-activated protein kinase (AMPK) in the effect of metformin because activation of AMPK with A769662 did not mimic metformin here. Furthermore, metformin was still inhibitory in AMKPα1- or AMPKβ1-deficient cells. The activity of NADH:ubiquinone oxidoreductase (complex I) was inhibited by metformin. Another complex I inhibitor, rotenone, mimicked the effect of metformin on pro-IL-1β and IL-10. LPS induced reactive oxygen species production, an effect inhibited by metformin or rotenone pretreatment. MitoQ, a mitochondrially targeted antioxidant, decreased LPS-induced IL-1β without affecting TNF-α. These results, therefore, implicate complex I in LPS action in macrophages.

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References

Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V . Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000; 49(12):2063-9. PMC: 2995498. DOI: 10.2337/diabetes.49.12.2063. View

Hawley S, Fullerton M, Ross F, Schertzer J, Chevtzoff C, Walker K . The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012; 336(6083):918-22. PMC: 3399766. DOI: 10.1126/science.1215327. View

Park S, Gammon S, Knippers J, Paulsen S, Rubink D, Winder W . Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. J Appl Physiol (1985). 2002; 92(6):2475-82. DOI: 10.1152/japplphysiol.00071.2002. View

Hirosumi J, Tuncman G, Chang L, Gorgun C, Uysal K, Maeda K . A central role for JNK in obesity and insulin resistance. Nature. 2002; 420(6913):333-6. DOI: 10.1038/nature01137. View

Hawley S, Boudeau J, Reid J, Mustard K, Udd L, Makela T . Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003; 2(4):28. PMC: 333410. DOI: 10.1186/1475-4924-2-28. View

Lambert A, Brand M . Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem. 2004; 279(38):39414-20. DOI: 10.1074/jbc.M406576200. View

Carroll K, Viollet B, Suttles J . AMPKα1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling. J Leukoc Biol. 2013; 94(6):1113-21. PMC: 3828606. DOI: 10.1189/jlb.0313157. View

Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V . Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol. 2011; 187(2):613-7. PMC: 3131480. DOI: 10.4049/jimmunol.1100613. View

Stephenne X, Foretz M, Taleux N, van der Zon G, Sokal E, Hue L . Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia. 2011; 54(12):3101-10. PMC: 3210354. DOI: 10.1007/s00125-011-2311-5. View

10.

Galic S, Fullerton M, Schertzer J, Sikkema S, Marcinko K, Walkley C . Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest. 2011; 121(12):4903-15. PMC: 3226000. DOI: 10.1172/JCI58577. View

11.

Lee H, Kim J, Kim H, Shong M, Ku B, Jo E . Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2012; 62(1):194-204. PMC: 3526026. DOI: 10.2337/db12-0420. View

12.

Moran A, Bundy B, Becker D, DiMeglio L, Gitelman S, Goland R . Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013; 381(9881):1905-15. PMC: 3827771. DOI: 10.1016/S0140-6736(13)60023-9. View

13.

Dashdorj A, Jyothi K, Lim S, Jo A, Nguyen M, Ha J . Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines. BMC Med. 2013; 11:178. PMC: 3750576. DOI: 10.1186/1741-7015-11-178. View

14.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

15.

Fullerton M, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen Z . Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013; 19(12):1649-54. PMC: 4965268. DOI: 10.1038/nm.3372. View

16.

Guo Y, Zhang Y, Hong K, Luo F, Gu Q, Lu N . AMPK inhibition blocks ROS-NFκB signaling and attenuates endotoxemia-induced liver injury. PLoS One. 2014; 9(1):e86881. PMC: 3901729. DOI: 10.1371/journal.pone.0086881. View

17.

Woo S, Xu H, Li H, Zhao Y, Hu X, Zhao J . Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS One. 2014; 9(3):e91111. PMC: 3956460. DOI: 10.1371/journal.pone.0091111. View

18.

Kim J, Kwak H, Cha J, Jeong Y, Rhee S, Kim K . Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J Biol Chem. 2014; 289(33):23246-23255. PMC: 4132821. DOI: 10.1074/jbc.M114.577908. View

19.

Zarrouk M, Finlay D, Foretz M, Viollet B, Cantrell D . Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells. PLoS One. 2014; 9(9):e106710. PMC: 4152329. DOI: 10.1371/journal.pone.0106710. View

20.

Meng S, Cao J, He Q, Xiong L, Chang E, Radovick S . Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex. J Biol Chem. 2014; 290(6):3793-802. PMC: 4319043. DOI: 10.1074/jbc.M114.604421. View