Horm Metab Res 2011; 43(8): 537-544
DOI: 10.1055/s-0031-1277227
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Effects of Adiponectin in TNF-α, IL-6, and IL-10 Cytokine Production from Coronary Artery Disease Macrophages

E. Kyriazi1 , 2 , P. C. Tsiotra1 , E. Boutati2 , I. Ikonomidis3 , K. Fountoulaki3 , E. Maratou1 , J. Lekakis3 , G. Dimitriadis2 , D. T. Kremastinos3 , S. A. Raptis1 , 2
  • 1Hellenic National Center for the Research, Prevention and Treatment of Diabetes Mellitus and its Complications (H.N.D.C), Athens, Greece
  • 22nd Department of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, “Attikon” University General Hospital, Athens, Greece
  • 32nd Department of Cardiology, Athens University Medical School, “Attikon” University General Hospital, Athens, Greece
Further Information

Publication History

received 04.11.2011

accepted 19.04.2011

Publication Date:
30 May 2011 (online)

Abstract

Adiponectin, an adipose tissue secreted protein, exhibits anti-inflammatory and antiatherogenic properties. We examined the effects of the globular and full-length adiponectin on cytokine production in macrophages derived from Coronary Artery Disease (CAD) patients and control individuals. Adiponectin's effects in human macrophages upon lipopolysaccharide (LPS) treatment were also examined. Full length adiponectin acted differently on TNF-α and IL-6 production by upregulating TNF-α and IL-6 protein production, but not their mRNA expression. Additionally, full length adiponectin was unable to abrogate LPS proinflammatory effect in TNF-α and IL-6 mRNA expression in CAD and NON-CAD macrophages. In contrast, globular adiponectin appeared to have proinflammatory properties by potently upregulating TNF-α and IL-6 mRNA and protein secretion in human macrophages while subsequently rendered cells resistant to further proinflammatory stimuli. Moreover, both forms of adiponectin powerfully suppressed scavenger MSR-AI mRNA expression and augmented IL-10 protein release, both occurring independently of the presence of LPS or CAD. These data indicate that adiponectin could potentially protect human macrophages via the elevated IL-10 secretion and the suppression of MSR-AI expression. It can also be protective in CAD patients since the reduced adiponectin-induced IL-6 release in CAD macrophages compared to controls, could be beneficial in the development of inflammation related atherosclerosis.

References

  • 1 Ross R. Atherosclerosis – an inflammatory disease.  N Engl J Med. 1999;  340 115126
  • 2 Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis.  Nat Rev Cardiol. 2009;  6 399-409
  • 3 Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice.  Circ J. 2010;  74 213-220
  • 4 Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue.  J Clin Invest. 2003;  112 1785-1788
  • 5 Matsuzawa Y. Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease.  Nat Clin Pract Cardiovasc Med. 2006;  3 35-42
  • 6 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.  Nat Rev Immunol. 2006;  6 772-783
  • 7 Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study.  Circulation. 1983;  67 968-977
  • 8 Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
  • 9 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin in obesity.  Biochem Biophys Res Comm. 1999;  257 79-83
  • 10 Waki H, Yamauchi T, Kamon J, Kita S, Ito Y, Hada Y, Uchida S, Tsuchida A, Takekawa S, Kadowaki T. Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell-line THP-1.  Endocrinology. 2005;  146 790-796
  • 11 Lavoie V, Kernaleguen AE, Charron G, Farhat N, Cossette M, Mamarbachi AM, Allen BG, Rhéaume E, Tardif JC. Functional Effects of Adiponectin on Endothelial Progenitor Cells.  Obesity (Silver Spring). 2011;  19 722-728
  • 12 Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.  Nat Med. 2002;  8 1288-1295
  • 13 Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.  Nature. 2003;  423 762-769
  • 14 Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y. Association of hypoadiponectinemia with coronary artery disease in men.  Arterioscler Thromb Vasc Biol. 2003;  23 85-89
  • 15 Stumvoll M, Tschritter O, Fritsche A, Taiger H, Renn W, Weisser M, Machicao F, Häring H. Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity.  Diabetes. 2002;  51 37-41
  • 16 Bacci S, Menzaghi C, Ercolino T, Ma X, Rauseo A, Salvemini L, Vigna C, Fanelli R, Di Mario U, Doria A, Trischitta V. The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients.  Diabetes Care. 2004;  27 2015-2020
  • 17 Halvatsiotis I, Tsiotra PC, Ikonomidis I, Kollias A, Mitrou P, Maratou E, Boutati E, Lekakis J, Dimitriadis G, Economopoulos T, Kremastinos DT, Raptis SA. Genetic variation in the adiponectin receptor 2 (ADIPOR2) gene is associated with coronary artery disease and increased ADIPOR2 expression in peripheral monocytes.  Cardiovasc Diabetol. 2010;  9 10
  • 18 Libby P, Geng YJ, Aikawa M, Schoenbeck U, Mach F, Clinton SK, Sukhova GK, Lee RT. Macrophages and atherosclerotic plaque stability.  Curr Opin Lipidol. 1996;  7 330-335
  • 19 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue.  J Clin Invest. 2003;  112 1796-1808
  • 20 Chinetti G, Zawadski JC, Fruchart B, Staels B. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR.  Biochem Biophys Res Commun. 2004;  314 151-158
  • 21 Kollias A, Tsiotra PC, Ikonomidis I, Maratou E, Mitrou P, Kyriazi E, Boutati E, Lekakis J, Economopoulos T, Kremastinos DT, Dimitriadis G, Raptis SA. Adiponectin levels and expression of adiponectin receptors in isolated monocytes from overweight patients with coronary artery disease.  Cardiovasc Diabetol. 2011;  10 14
  • 22 Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages.  Blood. 2000;  96 1723-1732
  • 23 Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes.  Biochem Biophys Res Commun. 2004;  323 630-635
  • 24 Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophage.  Circulation. 2004;  109 2046-2049
  • 25 Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin.  Circulation. 1999;  100 2473-2476
  • 26 Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages.  Circulation. 2001;  103 1057-1063
  • 27 Tian L, Luo N, Klein RL, Chung BH, Garvey WT, Fu Y. Adiponectin reduces lipid accumulation in macrophage foam cells.  Atherosclerosis. 2009;  202 152-161
  • 28 Luo N, Liu J, Chung BH, Yang Q, Klein RL, Garvey WT, Fu Y. Macrophage adiponectin expression improves insulin sensitivity and protects against inflammation and atherosclerosis.  Diabetes. 2010;  59 791-799
  • 29 Ajuwon KM, Spurlock ME. Adiponectin inhibits LPS-induced NF-kappaB activation and IL-6 production and increases PPARgamma2 expression in adipocytes.  Am J Physiol Regul Integr Comp Physiol. 2005;  288 R1220-R1225
  • 30 Tsiotra PC, Tsigos C, Yfanti E, Anastasiou E, Vikentiou M, Psarra K, Papasteriades C, Raptis SA. Visfatin, TNF-alpha and IL-6 mRNA expression is increased in mononuclear cells from type 2 diabetic women.  Horm Metab Res. 2007;  39 758-763
  • 31 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.  Nat Med. 2001;  7 941-946
  • 32 Geng Y, Kodama T, Hansson GK. Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell formation.  Arterioscler Thromb. 1994;  14 798-806
  • 33 Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.  Circulation. 2002;  106 2767-2770
  • 34 Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME. Adiponectin differentially regulates cytokines in porcine macrophages.  Biochem Biophys Res Commun. 2004;  316 924-929
  • 35 Frystyk J, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A. Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications.  Diabetologia. 2005;  48 1911-1918
  • 36 Abke S, Neumeier M, Weigert J, Wehrwein G, Eggenhofer E, Schäffler A, Maier K, Aslanidis C, Schölmerich J, Buechler C. Adiponectin-induced secretion of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) is impaired in monocytes from patients with type I diabetes.  Cardiovasc Diabetol. 2006;  5 17
  • 37 Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin.  Endocrinology. 2007;  148 5478-5486
  • 38 Park PH, McMullen MR, Huang H, Thakur V, Nagy LE. Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-alpha (TNF-alpha) expression via ERK1/2 activation and Egr-1 expression: role of TNF-alpha in adiponectin-stimulated interleukin-10 production.  J Biol Chem. 2007;  282 21695-21703
  • 39 Weigert J, Neumeier M, Wanninger J, Wurm S, Kopp A, Schober F, Filarsky M, Schäffler A, Zeitoun M, Aslanidis C, Buechler C. Reduced response to adiponectin and lower abundance of adiponectin receptor proteins in type 2 diabetic monocytes.  FEBS Lett. 2008;  582 1777-1782
  • 40 Tsatsanis C, Zacharioudaki V, Androulidaki A, Dermitzaki E, Charalampopoulos I, Minas V, Gravanis A, Margioris AN. Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other proinflammatory stimuli.  Biochem Biophys Res Commun. 2005;  335 1254-1263

Correspondence

P. C. TsiotraPhD 

Molecular Biology Lab.

Hellenic National Center for the

Research, Prevention and

Treatment of Diabetes Mellitus

and its Complications (H.N.D.C)

Ploutarchou 3

10675 Athens

Greece

Phone: +30/210/5832 485+ 30/210/7295 160

Fax: +30/210/5326 454+ 30/210/7295 168

Email: ytsiotra@hndc.gr

    >