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Diabetologia
Published in: Diabetologia 11/2010

01-11-2010

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

Authors: A. Nerstedt, A. Johansson, C. X. Andersson, E. Cansby, U. Smith, M. Mahlapuu

Published in: Diabetologia | Issue 11/2010

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Abstract

Aim/hypothesis

The aim of the study was to examine the possible role of AMP-activated protein kinase (AMPK) in the regulation of the inflammatory response induced by cytokine action in human liver cells.

Methods

IL-6-stimulated expression of the genes for acute-phase response markers serum amyloid A (SAA1, SAA2) and haptoglobin (HP) in the human hepatocarcinoma cell line HepG2 were quantified after modulation of AMPK activity by pharmacological agonists (5-amino-4-imidazole-carboxamideriboside [AICAR], metformin) or by using small interfering (si) RNA transfection. The intracellular signalling pathway mediating the effect of AMPK on IL-6-stimulated acute-phase marker expression was characterised by assessing the phosphorylation levels of the candidate protein signal transducer and activator of transcription 3 (STAT3) in response to AMPK agonists.

Results

AICAR and metformin markedly blunt the IL-6-stimulated expression of SAA cluster genes as well as of haptoglobin in a dose-dependent manner. Moreover, the repression of AMPK activity by siRNA significantly reversed the inhibition of SAA expression by both AICAR and metformin, indicating that the effect of the agonists is dependent on AMPK. For the first time we show that AMPK appears to regulate IL-6 signalling by directly inhibiting the activation of the main downstream target of IL-6, STAT3.

Conclusions/interpretation

We provide evidence for a key function of AMPK in suppression of the acute-phase response caused by the action of IL-6 in liver, suggesting that AMPK may act as an intracellular link between chronic low-grade inflammation and metabolic regulation in peripheral metabolic tissues.
Appendix
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Literature
1.
2.
Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115:1111–1119PubMed
3.
4.
Hawley SA, Boudeau J, Reid JL et al (2003) 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 2:28CrossRefPubMed
5.
Woods A, Dickerson K, Heath R et al (2005) Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2:21–33CrossRefPubMed
6.
Scott JW, Hawley SA, Green KA et al (2004) CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 113:274–284PubMed
7.
Long YC, Zierath JR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116:1776–1783CrossRefPubMed
8.
Zhao X, Zmijewski JW, Lorne E et al (2008) Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295:L497–L504CrossRefPubMed
9.
Kim TB, Kim SY, Moon KA et al (2007) Five-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates poly(I:C)-induced airway inflammation in a murine model of asthma. Clin Exp Allergy 37:1709–1719CrossRefPubMed
10.
Carter AM, Bennett CE, Bostock JA, Grant PJ (2005) Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus. Diabet Med 22:1282–1284CrossRefPubMed
11.
Mohanty P, Aljada A, Ghanim H et al (2004) Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 89:2728–2735CrossRefPubMed
12.
Hattori Y, Suzuki K, Hattori S, Kasai K (2006) Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 47:1183–1188CrossRefPubMed
13.
Peairs A, Radjavi A, Davis S et al (2009) Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells. Clin Exp Immunol 156:542–551CrossRefPubMed
14.
Kuo CL, Ho FM, Chang MY, Prakash E, Lin WW (2008) Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. J Cell Biochem 103:931–940CrossRefPubMed
15.
Jhun BS, Jin Q, Oh YT et al (2004) 5-Aminoimidazole-4-carboxamide riboside suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of phosphatidylinositol 3-kinase/Akt activation in RAW 264.7 murine macrophages. Biochem Biophys Res Commun 318:372–380CrossRefPubMed
16.
Sag D, Carling D, Stout RD, Suttles J (2008) Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 181:8633–8641PubMed
17.
Miller EJ, Li J, Leng L et al (2008) Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451:578–582CrossRefPubMed
18.
Watt MJ, Dzamko N, Thomas WG et al (2006) CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12:541–548CrossRefPubMed
19.
Carey AL, Steinberg GR, Macaulay SL et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55:2688–2697CrossRefPubMed
20.
Kelly M, Keller C, Avilucea PR et al (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320:449–454CrossRefPubMed
21.
Mahlapuu M, Johansson C, Lindgren K et al (2004) Expression profiling of the gamma-subunit isoforms of AMP-activated protein kinase suggests a major role for gamma3 in white skeletal muscle. Am J Physiol Endocrinol Metab 286:E194–E200CrossRefPubMed
22.
Carlsson L, Nilsson I, Oscarsson J (1998) Hormonal regulation of liver fatty acid-binding protein in vivo and in vitro: effects of growth hormone and insulin. Endocrinology 139:2699–2709CrossRefPubMed
23.
Cheung PC, Salt IP, Davies SP, Hardie DG, Carling D (2000) Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem J 346(Pt 3):659–669CrossRefPubMed
24.
do Nascimento CO, Hunter L, Trayhurn P (2004) Regulation of haptoglobin gene expression in 3T3-L1 adipocytes by cytokines, catecholamines, and PPARgamma. Biochem Biophys Res Commun 313:702–708CrossRefPubMed
25.
Ramadori G, Van Damme J, Rieder H, Meyer zum Buschenfelde KH (1988) Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor-alpha. Eur J Immunol 18:1259–1264CrossRefPubMed
26.
Corton JM, Gillespie JG, Hawley SA, Hardie DG (1995) 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229:558–565CrossRefPubMed
27.
Brunmair B, Staniek K, Gras F et al (2004) Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53:1052–1059CrossRefPubMed
28.
Carling D, Sanders MJ, Woods A (2008) The regulation of AMP-activated protein kinase by upstream kinases. Int J Obes (Lond) 32(Suppl 4):S55–S59CrossRef
29.
Franckhauser S, Elias I, Rotter Sopasakis V et al (2008) Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 51:1306–1316CrossRefPubMed
30.
Ruderman NB, Keller C, Richard AM et al (2006) Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55(Suppl 2):S48–S54CrossRefPubMed
31.
Steinberg GR, Michell BJ, van Denderen BJ et al (2006) Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 4:465–474CrossRefPubMed
32.
Andersson CX, Sopasakis VR, Wallerstedt E, Smith U (2007) Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes. J Biol Chem 282:9430–9435CrossRefPubMed
33.
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20CrossRefPubMed
34.
Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F (2000) SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. J Biol Chem 275:12848–12856CrossRefPubMed
35.
Senn JJ, Klover PJ, Nowak IA et al (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278:13740–13746CrossRefPubMed
36.
Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434–5446CrossRefPubMed
37.
Ueki K, Kondo T, Tseng YH, Kahn CR (2004) Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci USA 101:10422–10427CrossRefPubMed
38.
Pickup JC, Mattock MB, Chusney GD, Burt D (1997) NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40:1286–1292CrossRefPubMed
39.
Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751PubMed
40.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614CrossRefPubMed
41.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334CrossRefPubMed
42.
Yamada Y, Webber EM, Kirillova I, Peschon JJ, Fausto N (1998) Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28:959–970CrossRefPubMed
43.
Campbell JS, Prichard L, Schaper F et al (2001) Expression of suppressors of cytokine signaling during liver regeneration. J Clin Invest 107:1285–1292CrossRefPubMed
44.
Cardellini M, Perego L, D’Adamo M et al (2005) C-174G polymorphism in the promoter of the interleukin-6 gene is associated with insulin resistance. Diab Care 28:2007–2012CrossRef
45.
Febbraio MA, Pedersen BK (2002) Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J 16:1335–1347CrossRefPubMed
46.
Steensberg A, Fischer CP, Sacchetti M et al (2003) Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans. J Physiol 548:631–638CrossRefPubMed
47.
Choy EH, Isenberg DA, Garrood T et al (2002) Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46:3143–3150CrossRefPubMed
48.
Klover PJ, Zimmers TA, Koniaris LG, Mooney RA (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52:2784–2789CrossRefPubMed
49.
Kim HJ, Higashimori T, Park SY et al (2004) Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53:1060–1067CrossRefPubMed
50.
Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51:3391–3399CrossRefPubMed
51.
Vincent MF, Bontemps F, Van den Berghe G (1992) Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem J 281(Pt 1):267–272PubMed
52.
Inoue H, Ogawa W, Asakawa A et al (2006) Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab 3:267–275CrossRefPubMed
53.
Kinoshita S, Ogawa W, Okamoto Y et al (2008) Role of hepatic STAT3 in the regulation of lipid metabolism. Kobe J Med Sci 54:E200–E208PubMed
Metadata
Title
AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)
Authors
A. Nerstedt
A. Johansson
C. X. Andersson
E. Cansby
U. Smith
M. Mahlapuu
Publication date
01-11-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1856-z

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