Horm Metab Res 2008; 40(1): 8-12
DOI: 10.1055/s-2007-1004515
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Long-term Interleukin-1α Treatment Inhibits Insulin Signaling via IL-6 Production and SOCS3 Expression in 3T3-L1 Adipocytes

T. Uno 1 , J. He 1 , I. Usui 1 , Y. Kanatani 1 , A. Bukhari 1 , S. Fujisaka 1 , Y. Yamazaki 1 , H. Suzuki 1 , M. Iwata 1 , M. Ishiki 1 , M. Urakaze 1 , T. Haruta 1 , H. Ogawa 1 , M. Kobayashi 1
  • 1First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
Further Information

Publication History

received 26.02.2007

accepted 09.07.2007

Publication Date:
17 December 2007 (online)

Abstract

Proinflammatory cytokines are well-known to inhibit insulin signaling to result in insulin resistance. IL-1α is also one of the proinflammatory cytokines, but the mechanism of how IL-1α induces insulin resistance remains unclear. We have now examined the effects of IL-1α on insulin signaling in 3T3-L1 adipocytes. Prolonged IL-1α treatment for 12 to 24 hours partially decreased the protein levels as well as the insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt phosphorylation. mRNA for SOCS3, an endogenous inhibitor of insulin signaling, was dramatically augmented 4 hours after IL-1α treatment. Concomitantly, the level of IL-6 in the medium and STAT3 phosphorylation were increased by the prolonged IL-1α treatment. Addition of anti-IL-6 neutralizing antibody to the medium or overexpression of dominant-negative STAT3 decreased the IL-1α-stimulated STAT3 activation and SOCS3 induction, and ameliorated insulin signaling. These results suggest that the IL-1α-mediated deterioration of insulin signaling is largely due to the IL-6 production and SOCS3 induction in 3T3-L1 adipocytes.

References

  • 1 Kahn BB, Flier JS. Obesity and insulin resistance.  J Clin Invest. 2000;  106 473-481
  • 2 Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.  Science. 2004;  306 457-461
  • 3 Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1.  Mol Endocrinol. 2000;  14 783-794
  • 4 Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex.  J Biol Chem. 2002;  277 48115-48121
  • 5 Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).  J Biol Chem. 2000;  275 9047-9054
  • 6 Pirola L, Johnston AM, Obberghen E Van. Modulation of insulin action.  Diabetologia. 2004;  47 170-184
  • 7 Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X.  Diabetologia. 1997;  40 1286-1292
  • 8 Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.  Science. 1996;  271 665-668
  • 9 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.  J Clin Invest. 2003;  112 1821-1830
  • 10 He J, Usui I, Ishizuka K, Kanatani Y, Hiratani K, Iwata M, Bukhari A, Haruta T, Sasaoka T, Kobayashi M. Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes.  Mol Endocrinol. 2006;  20 114-124
  • 11 Salmenniemi U, Ruotsalainen E, Pihlajamaki J, Vauhkonen I, Kainulainen S, Punnonen K, Vanninen E, Laakso M. Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome.  Circulation. 2004;  110 3842-3848
  • 12 Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.  Diabetes. 2003;  52 812-817
  • 13 Dinarello CA, Wolff SM. The role of interleukin-1 in disease.  N Engl J Med. 1993;  328 106-113
  • 14 Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2.  J Biol Chem. 2002;  277 42394-42398
  • 15 Shi H, Tzameli I, Bjorbaek C, Flier JS. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling.  J Biol Chem. 2004;  279 34733-34740
  • 16 Ueki K, Kondo T, Kahn CR. 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. 2004;  24 5434-5446
  • 17 Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T. Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes.  Circulation. 1998;  98 346-352
  • 18 Takano A, Usui I, Haruta T, Kawahara J, Uno T, Iwata M, Kobayashi M. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin.  Mol Cell Biol. 2001;  21 5050-5062
  • 19 Shulman GI. Cellular mechanisms of insulin resistance.  J Clin Invest. 2000;  106 171-176

Correspondence

I. Usui

First Department of Internal Medicine

Faculty of Medicine

University of Toyama

2630 Sugitani

930-0194 Toyama

Japan

Phone: +81/76/434 72 87

Fax: +81/76/434 50 25

Email: isaousui-tym@umin.ac.jp

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