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)
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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.
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AMPK exerted its anti-inflammatory roles on the vasculature partially via the inhibition of adhesion molecules and chemoattractants by regulating signal transducer and activator of transcription 3, of nuclear factor kappa B, and p300 pathways.
“Indeed, studies have uncovered that AMPK exerted its anti-inflammatory roles on the vasculature partially via the inhibition of adhesion molecules and chemoattractants [248,249,252,253] by regulating signal transducer and activator of transcription 3, of nuclear factor kappa B, and p300 pathways [254,255,256].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [252]
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Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199 · see citing works
C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus
Pradhan, A. D. (2001) · JAMA · doi:10.1001/jama.286.3.327 · Cited by 4,433 · see citing works
Inflammation, stress, and diabetes
Wellen, K. E., & Hotamisligil, G. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25102 · Cited by 4,143 · see citing works
Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · see citing works
Protection from obesity-induced insulin resistance in mice lacking TNF-α function
Uysal, K. T., Wiesbrock, S. M., Marino, M. W., & Hotamisligil, G. S. (1997) · Nature · doi:10.1038/39335 · Cited by 2,234 · see citing works
Kern, P. A., Ranganathan, S., Li, C., Wood, L., & Ranganathan, G. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.5.e745 · Cited by 1,883 · see citing works
Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,666 · see citing works
Woods, A., Dickerson, K., Heath, R. B., Hong, S. P., Momcilovic, M., Johnstone, S. R., Carlson, M., & Carling, D. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.005 · Cited by 1,382 · see citing works
Corton, J. M., Gillespie, J. G., Hawley, S. A., & Hardie, D. G. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20498.x · Cited by 1,232 · see citing works
Pickup, J. C., Mattock, M. B., Chusney, G. D., & Burt, D. J. (1997) · Diabetologia · doi:10.1007/s001250050822 · Cited by 1,231 · see citing works
AMP-activated protein kinase signaling in metabolic regulation
Long, Y. C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29044 · Cited by 1,097 · see citing works
Carey, A. L., Steinberg, G. R., Macaulay, S. L., Thomas, W. G., Holmes, A. G., Ramm, G., Prelovsek, O., Hohnen-Behrens, C., Watt, M. J., James, D. E., et al. (2006) · Diabetes · doi:10.2337/db05-1404 · Cited by 898 · see citing works
Interleukin-6 induces cellular insulin resistance in hepatocytes.
Senn, J. J., Klover, P. J., Nowak, I. A., & Mooney, R. A. (2002) · Diabetes · doi:10.2337/diabetes.51.12.3391 · Cited by 883 · see citing works
Muscle‐derived interleukin‐6: mechanisms for activation and possible biological roles
FEBBRAIO, M. A., & PEDERSEN, B. K. (2002) · The FASEB Journal · doi:10.1096/fj.01-0876rev · Cited by 875 · see citing works
Sağ, D., Carling, D., Stout, R. D., & Suttles, J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.12.8633 · Cited by 798 · see citing works
Scott, J. W., Hawley, S. A., Green, K. A., Anis, M., Stewart, G., Scullion, G. A., Norman, D. G., & Hardie, D. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19874 · Cited by 754 · see citing works
Ueki, K., Kondo, T., & Kahn, C. R. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5434-5446.2004 · Cited by 686 · see citing works
Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding
CHEUNG, P. C. F., SALT, I. P., DAVIES, S. P., HARDIE, D. G., & CARLING, D. (2000) · Biochemical Journal · doi:10.1042/bj3460659 · Cited by 637 · see citing works
Senn, J. J., Klover, P. J., Nowak, I. A., Zimmers, T. A., Koniaris, L. G., Furlanetto, R. W., & Mooney, R. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210689200 · Cited by 620 · see citing works
Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo
Kim, H.-J., Higashimori, T., Park, S.-Y., Choi, H., Dong, J., Kim, Y.-J., Noh, H.-L., Cho, Y.-R., Cline, G., Kim, Y.-B., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1060 · Cited by 534 · see citing works
Choy, E. H. S., Isenberg, D. A., Garrood, T., Farrow, S., Ioannou, Y., Bird, H., Cheung, N., Williams, B., Hazleman, B., Price, R., et al. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10623 · Cited by 526 · see citing works
Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I
Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhäusl, W., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1052 · Cited by 521 · see citing works
Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice
Klover, P. J., Zimmers, T. A., Koniaris, L. G., & Mooney, R. A. (2003) · Diabetes · doi:10.2337/diabetes.52.11.2784 · Cited by 488 · see citing works
Hattori, Y., Suzuki, K., Hattori, S., & Kasai, K. (2006) · Hypertension · doi:10.1161/01.hyp.0000221429.94591.72 · Cited by 487 · see citing works
Miller, E. J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R., & Young, L. H. (2008) · Nature · doi:10.1038/nature06504 · Cited by 429 · see citing works
Steinberg, G. R., Michell, B. J., van Denderen, B. J. W., Watt, M. J., Carey, A. L., Fam, B. C., Andrikopoulos, S., Proietto, J., Görgün, C. Z., Carling, D., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.11.005 · Cited by 418 · see citing works
Schmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., & Schaper, F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12848 · Cited by 388 · see citing works
Ueki, K., Kondo, T., Tseng, Y., & Kahn, C. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402511101 · Cited by 382 · see citing works
Evidence for a Potent Antiinflammatory Effect of Rosiglitazone
Mohanty, P., Aljada, A., Ghanim, H., Hofmeyer, D., Tripathy, D., Syed, T., Al-Haddad, W., Dhindsa, S., & Dandona, P. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-032103 · Cited by 375 · see citing works
Zhao, X., Zmijewski, J. W., Lorne, E., Liu, G., Park, Y.-J., Tsuruta, Y., & Abraham, E. H. (2008) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.90210.2008 · Cited by 300 · see citing works
Role of hepatic STAT3 in brain-insulin action on hepatic glucose production
Inoue, H., Ogawa, W., Asakawa, A., Okamoto, Y., Nishizawa, A., Matsumoto, M., Teshigawara, K., Matsuki, Y., Watanabe, E., Hiramatsu, R., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.009 · Cited by 294 · see citing works
AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise.
Kelly, M., Keller, C., Avilucea, P. R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A. K., Pedersen, B. K., et al. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.05.188 · Cited by 289 · see citing works
The regulation of AMP-activated protein kinase by upstream kinases
Carling, D., Sanders, M. J., & Woods, A. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.124 · Cited by 286 · see citing works
Ramadori, G., Van Damme, J., Rieder, H., & Zum Büschenfelde, K. M. (1988) · European Journal of Immunology · doi:10.1002/eji.1830180817 · Cited by 284 · see citing works
CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK
Watt, M. J., Dzamko, N. L., Thomas, W. G., Rose‐John, S., Ernst, M., Carling, D., Kemp, B. E., Febbraio, M. A., & Steinberg, G. R. (2006) · Nature Medicine · doi:10.1038/nm1383 · Cited by 275 · see citing works
Yamada, Y., Webber, E. M., Kirillova, I., Peschon, J. J., & Fausto, N. (1998) · Hepatology · doi:10.1002/hep.510280410 · Cited by 260 · see citing works
AMP-activated protein kinase: balancing the scales
Carling, D. (2004) · Biochimie · doi:10.1016/j.biochi.2004.10.017 · Cited by 201 · see citing works
Interleukin-6 Regulation of AMP-Activated Protein Kinase
Ruderman, N. B., Keller, C., Richard, A.-M. T., Saha, A. K., Luo, Z., Xiang, X., Giralt, M., Ritov, V. B., Menshikova, E. V., Kelley, D. E., et al. (2006) · Diabetes · doi:10.2337/db06-s007 · Cited by 190 · see citing works
Mahlapuu, M., Johansson, C., Lindgren, K., Hjälm, G., Barnes, B. R., Krook, A., Zierath, J., Andersson, L., & Marklund, S. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00147.2003 · Cited by 169 · see citing works
Self-citationOverexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice
Franckhauser, S., Elias, I., Sopasakis, V. R., Ferré, T., Nagaev, I., Andersson, C. X., Agudo, J., Ruberte, J., Bosch, F., & Smith, U. (2008) · Diabetologia · doi:10.1007/s00125-008-0998-8 · Cited by 166 · see citing works
Self-citationExpression of suppressors of cytokine signaling during liver regeneration
Campbell, J. S., Prichard, L., Schaper, F., Schmitz, J., Stephenson-Famy, A., Rosenfeld, M. E., Argast, G. M., Heinrich, P. C., & Fausto, N. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11867 · Cited by 156 · see citing works
Steensberg, A., Fischer, C. P., Sacchetti, M., Keller, C., Osada, T., Schjerling, P., van Hall, G., Febbraio, M. A., & Pedersen, B. K. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00631.x · Cited by 152 · see citing works
Steensberg, A., Fischer, C. P., Sacchetti, M., Keller, C., Osada, T., Schjerling, P., van Hall, G., Febbraio, M. A., & Pedersen, B. K. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.032938 · Cited by 152 · see citing works
Jhun, B. S., Jin, Q., Oh, Y. T., Kim, S. S., Kong, Y., Cho, Y. H., Ha, J., Baik, H. H., & Kang, I. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.04.035 · Cited by 108 · see citing works
Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells
Peairs, A., Radjavi, A., Davis, S., Li, L., Ahmed, A. A., Giri, S., & Reilly, C. M. (2009) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2009.03924.x · Cited by 106 · see citing works
C-174G Polymorphism in the Promoter of the Interleukin-6 Gene Is Associated With Insulin Resistance
Cardellini, M., Perego, L., D’Adamo, M., Marini, M. A., Procopio, M. C., Hribal, M. L., Andreozzi, F., Frontoni, S., Giacomelli, M., Paganelli, M., et al. (2005) · Diabetes Care · doi:10.2337/diacare.28.8.2007 · Cited by 83 · see citing works
Kuo, C.-L., Ho, F., Chang, M.-Y., Prakash, E., & Lin, W. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21466 · Cited by 82 · see citing works
Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes
Vincent, M. F., Bontemps, F., & den Berghe, G. V. (1992) · Biochemical Journal · doi:10.1042/bj2810267 · Cited by 81 · see citing works
do Nascimento, C. O., Hunter, L., & Trayhurn, P. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.12.008 · Cited by 75 · see citing works
Carter, A. M., Bennett, C. E., Bostock, J. A., & Grant, P. J. (2005) · Diabetic Medicine · doi:10.1111/j.1464-5491.2005.01632.x · Cited by 66 · see citing works
Insulin Antagonizes Interleukin-6 Signaling and Is Anti-inflammatory in 3T3-L1 Adipocytes
Andersson, C. X., Sopasakis, V. R., Wallerstedt, E., & Smith, U. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609980200 · Cited by 42 · see citing works
Self-citationRole of hepatic STAT3 in the regulation of lipid metabolism.
Kinoshita, S., Ogawa, W., Okamoto, Y., Takashima, M., Inoue, H., Matsuki, Y., Watanabe, E., Hiramatsu, R., & Kasuga, M. (2008) · PubMed · doi:10.24546/81000870 · Cited by 42 · see citing works
Carlsson, L., Nilsson, I. E. K., & Oscarsson, J. (1998) · Endocrinology · doi:10.1210/endo.139.6.6041 · Cited by 40 · see citing works
Kim, T., Kim, S.-T., Moon, K. A., Park, C. ‐., Jang, M. K., Yun, E. S., Cho, Y. S., Moon, H., & Lee, K. ‐. (2007) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2007.02812.x · Cited by 28 · see citing works
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Vasamsetti, S. B., Karnewar, S., Kanugula, A. K., Thatipalli, A. R., Kumar, J. M., & Kotamraju, S. (2015) · Diabetes · doi:10.2337/db14-1225 · Cited by 397 · see citing works
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Wu, S., & Zou, M.-H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144987 · Cited by 286 · see citing works
Cufí, S., Vazquez-Martin, A., Oliveras-Ferraros, C., Martin-Castillo, B., Joven, J., & Menendez, J. A. (2010) · Cell Cycle · doi:10.4161/cc.9.22.14048 · Cited by 216 · see citing works
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Gongol, B., Marin, T., Peng, I.-C., Woo, B., Martin, M., King, S., Sun, W., Johnson, D. A., Chien, S., & Shyy, J. Y.-J. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222051110 · Cited by 61 · see citing works
- Authors
- Nerstedt, A., Johansson, A., Andersson, C. X., Cansby, E., Smith, U., & Mahlapuu, M.
- Affiliations
- University of Gothenburg (SE)
- Corresponding author
- Mahlapuu, M.
- Venue
- Diabetologia
- Published
- 2010-07-24
- Volume
- 53
- Issue
- 11
- Pages
- 2406-2416
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2026231752
- Cited by
- 106
- References
- 54
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 9 · 2013: 15 · 2012: 10
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- European Foundation for the Study of Diabetes
- Stiftelsen för Strategisk Forskning
- Novo Nordisk
- Vetenskapsrådet
- Svenska Läkaresällskapet
- Stiftelsen Längmanska Kulturfonden
- Novo Nordisk Fonden
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- AMPK, IL-6 signaling, STAT3 phosphorylation, acute phase response, serum amyloid A, haptoglobin, hepatocytes, AICAR, metformin, low-grade inflammation, metabolic regulation, liver inflammation
- MeSH terms
- Aminoimidazole Carboxamide, Cell Survival, Cells, Cultured, Humans, Hypoglycemic Agents, Liver, Metformin, Phosphorylation, Ribonucleotides, Blotting, Western, Signal Transduction, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, RNA Interference, RNA, Small Interfering, STAT3 Transcription Factor, AMP-Activated Protein Kinases, Hep G2 Cells
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