Open Access

The ubiquitous interleukin-6: a time for reappraisal

Cardiovascular Diabetology20109:62

DOI: 10.1186/1475-2840-9-62

Received: 1 October 2010

Accepted: 11 October 2010

Published: 11 October 2010

Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine regulating humoral and cellular responses and playing a central role in inflammation and tissue injury. Its effects are mediated through interaction with its receptor complex, IL-6Rβ (also known as gp130). It plays an important role in the pathogenesis of coronary artery disease and large quantities of IL-6 are found in human atherosclerotic plaques. IL-6 levels positively correlate with higher all-cause mortality, unstable angina, left ventricular dysfunction, propensity to diabetes and its complications, hypertension, obesity and several types of cancer. IL-6 levels augmentation demonstrates a remarkable parallel with another biomarkers reflecting harmful processes, like tumor necrosis factor alpha, interleukins 8 and 18, YKL-40, C reactive protein and resistin. Due to these facts, IL-6 was classified as a noxious interleukin. Nonetheless, there are several facts that challenge this usually accepted point of view. Since IL-6 has also anti-inflammatory activity, it seems reasonable to assume that favorable aspects exist. These aspects are two: 1. protection against bacterial infections, inactivating proinflammatory mediators, mitigating the course of septic shock and inducing the production of cortisol; and 2. influence on insulin sensitivity during exercise; this aspect is even more important. During exercise IL-6 is synthesized and released by muscles, with enhanced insulin action immediately at early recovery. Skeletal muscle may be considered as an endocrine organ; contracting muscles produce IL-6 and release it into the blood exerting its effects on other organs. The increase in circulating levels of IL-6 after exercise is consistent and proportional to exercise duration, intensity, muscle mass involved and endurance capacity. Thus, the fascinating possibility that the plenteous beneficial health effects of exercise could be ultimately mediated by IL-6 merits further elucidation. Interleukins were termed "good" or "bad", probably due to a tendency to see things in black and white, with no gray area in between. Calling IL-6 "a molecule with both beneficial and destructive potentials" would be a more equitable approach. In the literary creatures of Dr. Jekyll and Mr. Hyde, a good and an evil personality are found in the same individual. IL-6 playing the role of Dr. Jekyll is emerging; the time for IL-6 reappraisal is coming.

Evidence continues to pile during the last two decades regarding the clinical relevance of laboratory predictors of pathophysiological events. These predictors are molecules, usually in the picogram (pg) range, called biomarkers. New and more specific biomarkers are currently isolated employing sophisticated bioinformatics approaches [1, 2]. A biomarker is defined as a biochemical characteristic that may be objectively quantified and evaluated as an indicator of normal biological processes, pathogenic events, or responses to pharmacological or other therapeutic interventions. Thus, biomarkers are classified into 3 different types: Type 0, which estimates the emergence or advance of a disease, Type 1, which measures responses to therapeutic interventions, and Type 2, which may be employed as surrogate clinical endpoints [3, 4].

In this context, interleukin-6 (IL-6) has gained a leading role. Its popularity is rooted on the fact that it can be defined either as a Type 0, 1 or 2 biomarker, depending on the given clinical setting. Thus, overlapping the 3 types of biomarkers, IL-6 attained a wide use in experimental and clinical studies. IL-6 is a multifunctional cytokine. It regulates humoral and cellular responses and plays a central role in inflammation and tissue injury. Its effects are mediated through interaction with its receptor complex, IL-6Rβ (also known as gp130) as a signaling subunit. This cytokine plays a very important role in the pathogenesis of coronary artery disease (CAD) [5]. Large quantities of IL-6 are found in human atherosclerotic plaques [6]. IL-6 levels are associated to higher all-cause mortality in elderly persons [7] and are elevated in patients with unstable angina compared with those with stable disease [8]. Moreover, patients with persistently elevated IL-6 levels demonstrate a worse in-hospital outcome following admission with unstable angina [9, 10], as well as left ventricular diastolic dysfunction in both clinical trials [11] and experimental animal models [12]. We have also shown that in CAD patients with angina pectoris and/or healed myocardial infarction (MI), a significantly higher risk for future cardiac morbility and mortality was found in the upper IL-6 quintile (odds ratio, 3.44; 95% CI 1.57-8.13) after a mean follow-up period of 6.3 years [13]. IL-6 is also elevated in experimental MI models [14].

Additionally, IL-6 seems to embody a negative role in both main types of diabetes. After adjustment for age, gender, body mass index, waist-to-hip ratio, sports, smoking, alcohol consumption and other variables, IL-6 emerges as an independent early predictor of type 2 diabetes mellitus (T2DM), preceding its clinical onset [15]. Type 1 diabetes mellitus (T1DM) young patients - even in good glycemic control - show higher levels of IL-6 and fibrinogen than controls [16]. It has been shown that postmenopausal women with T1DM present higher serum bioactive IL-6 levels than matched healthy controls [17] and that subjects with diabetic foot show higher IL-6 values in comparison with T2DM patients without diabetic foot complication [18]. Additionally, IL-6 polymorphism seems to be a genetic susceptibility factor for the progression of diabetic nephropathy [19, 20].

Besides its roles in the cardiovascular system and in regulation of glucose metabolism, IL-6 ubiquity is astonishing. Secreted by several types of cells, mainly macrophagues and T cells, the pleiotropic IL-6 is related to both immunoregulation and nonimmune physiological traits in most cell types and tissues outside the immune system [21]. Expressing a state of low grade chronic inflammation, IL-6 augmented levels have been reported to be directly related to the severity of sepsis [22], hypertension [23], poor survival among head and neck cancer patients [24], development of hairy cell leukemia [25], increased breast cancer risk in premenopausal women [26], intensity of inflammatory responses [2729], obesity [30, 31], increased insulin resistance [23, 3234], etc. In addition, IL-6 levels augmentation demonstrates a remarkable parallel with another biomarkers reflecting harmful processes, like tumor necrosis factor alpha (TNFα) [11, 35], interleukins 8 and 18 [5, 36], YKL-40 [37], C reactive protein (CRP) [3840], resistin [41], etc. A comprehensive review of IL-6 numerous and complex biological effects is beyond the scope of this article.

Based on the above facts, IL-6 appears to be involved in a long series of deleterious actions, and it was classified as a noxious or "bad" interleukin [5, 42]. Nonetheless, there are several facts that challenge this usually accepted point of view. A reconsideration is needed, as detailed hereinafter.

Curtails of interleukin research

The concept of IL-6 being a damaging factor has growth mainly on the basis of statistical correlations in clinical studies, in vitro cell culture studies at supraphysiological levels of IL-6 and animal models employing mice [43].

Several important points should be taken into consideration when performing interleukin research: 1) increased levels of a given IL, presenting statistical correlation with disease, does not necessarily imply causation; 2) these compounds are characterized by substantial redundancy in that different interleukins have similar and overlapping functions; 3) interleukins may stimulate secretion of other interleukins, enhancing or inhibiting each other; 4) interleukins possess 'paradoxical' effects, expressed as protective properties regarding a given system, whereas they may damage another system, and 5) protective or noxious effects of a given interleukin may be concentration-dependent [5, 42].

These general rules also pertain specifically to IL-6. Thus, studies "blaming" IL-6 based on statistical analyses or cell culture at high IL-6 concentrations could be partially biased by the mentioned intrinsic drawbacks. Regarding mice studies, it should be pointed out that comparative genomics research demonstrated that mouse and human IL-6 share only 42% aminoacid sequence identity [21]; hence, in this particular case extrapolation of mice findings to humans requires extreme caution.

Another problem that jeopardizes IL-6 research and may intricate IL-6 use as a bedside laboratory tool is the variability of its values. The established normal values are 1 pg/ml [44, 45], but they increase at several settings like a single high fat meal [46] physical activity [47], normal menstrual cycle [48], acute hyperglycemia [49] or during and after surgery [50]. Pregnancy represents a good example of this inconsistency: median values of 129 pg/ml were registered at delivery, decreasing to 58 pg/ml immediately afterward [51]. Moreover, during sepsis IL-6 may reach even much more higher values [52].

Beneficial effects

Besides its proinflammatory properties, IL-6 and IL-6-regulated acute-phase proteins show also anti-inflammatory activity [53, 54]. Then, it seems reasonable to assume that IL-6 is not such a bad guy. We will briefly comment two aspects related to IL-6 favorable actions: bacterial infections and its particular influence on insulin sensitivity during exercise.

The protective IL-6 effects in infections were described almost three decades ago. Sometimes the interpretation of the results may be controversial since it is debatable whether in sepsis IL-6 represents an inflammation marker and/or a mediator of immune defense responses. Despite discordant results, some issues seem to be rather consistent. In neonatal mouse models of Group B streptococcal disease IL-6 decreases TNFα production, as well as the expression of TNF receptors in macrophages [55, 56]; exogenous administration of IL-6 improved survival and complete inhibition of IL-6 resulted in a more rapid mortality [56]. IL-6 inactivates proinflammatory mediators and mitigates the course of septic shock [57]; it also induces the production of adrenocorticotropin and, in turn, cortisol, which is a potent anti-inflammatory hormone [58]. In mice infected with the intracellular pathogen Listeria monocytogenes, recombinant mouse IL-6 injected intraperitoneally before infection protected mice in a dose-dependent manner, resulting in decreased bacterial numbers in the spleen and liver; IL-6 played a role in early priming of the immune response to infection [59]. Anyway, it must be pointed out that these encouraging results are partially overshadowed by the lack of controlled clinical studies.

The second aspect - insulin metabolism during exercise - is even more important. The overwhelming in vitro findings linking IL-6 to increased insulin resistance may lack clinical relevance as in vivo human studies demonstrate that neither splanchnic glucose output nor isotopic tracer determined endogenous glucose production are increased by acute infusion of recombinant human IL-6 (rhIL-6) [43, 60]. During exercise IL-6 is synthesized and released by skeletal muscle [61] and its plasma concentrations may be increased as much as 100-fold [47] - in parallel with the intensity and duration of exercise - this represents a far greater increase than that of any other cytokine that has been measured [61]. In this context, it was shown that IL-6 is rapidly released into the circulation following exercise [47], with enhanced insulin action immediately at early recovery. The improved insulin sensitivity is probably mediated by adenosine monophosphate-activated protein kinase (AMPK) [62, 63].

In addition, rhIL-6 infusion during a hyperinsulinemic-euglycemic clamp in healthy humans does not effect the insulin-mediated suppression of endogenous glucose production, while increasing glucose infusion rate [64]. Exercise-induced improvement of insulin sensitivity is mainly a local phenomenon, occurring primarily in the exercised, rather than the rested, muscles. This was confirmed from experiments using both rodent and human models where muscles in only one limb have performed work prior to evaluation of insulin action in both limbs [63, 65]. In both types of trials the prior exercised leg takes up glucose to a far greater extent and with enhanced insulin sensitivity compared with the rested leg. The changes may be of small magnitude, but over time they become important at the whole body [63].

It has been demonstrated that signaling pathways from contracting muscles to other organs are not solely mediated by the nervous system, since electrical stimulation of paralyzed muscles in spinal-cord-injured patients induces many of the same physiological changes as in neurological healthy individuals [66]. Therefore, it was clear that some humoral factor must exist. IL-6 fulfils the criteria of being that factor, via AMPK activation [47, 54, 64].

Concluding comment

One of the more important proofs concerning the crucial importance of IL-6 emerges from an experimental rodent genetic model dated 3 quinquenniums ago. A targeted disruption of the IL-6 receptor complex gp130 was performed. Embryos homozygous for the gp130 mutation showed hypoplastic ventricular myocardium, reduced numbers of pluripotential cells - mainly hematopoietic progenitors - anemia and several additional abnormalities. The results indicate that gp130 plays a crucial role in myocardial development and hematopoiesis during embryogenesis [67].

Undesirable effects of IL-6 paharmacological blocking maybe reflected also in a clinical routine setting. In recent years, tocilizumab, a humanized anti-IL-6-receptor monoclonal antibody, was developed and successfully used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis [68]. Common adverse events of the therapy were gastrointestinal, nasopharyngeal, and upper-respiratory-tract infections. More serious adverse events - an anaphylactoid reaction and a gastrointestinal hemorrhage - were also reported [69]. These events are probably related to IL-6-receptor inhibition.

The key IL-6 positive action is its relationship with physical activity via enhancement of insulin-stimulated glucose disposal in humans in vivo [64, 70]. Skeletal muscle may then be considered as a newly discovered endocrine organ; contracting muscles produce IL-6 and release it into the blood [43, 47, 71] exerting its effects on other organs in a hormone-like fashion. The increase in circulating levels of IL-6 after exercise is a consistent finding, proportional to exercise duration, intensity of effort, the muscle mass involved in the mechanical work and the endurance capacity [71]. Thus, the fascinating possibility that the plenteous beneficial health effects of exercise could be ultimately mediated by IL-6 merits further elucidation.

Interleukins were termed or classified as "good" or "bad" [5, 13, 72], probably due to a tendency to see things in black and white, with no gray area in between. Calling IL-6 "a molecule with both beneficial and destructive potentials" [73] would be a more equitable approach. In the literary creatures of Dr. Jekyll and Mr. Hyde, a good and an evil personality are found in the same individual [74]. IL-6 playing the role of Dr. Jekyll is emerging; the time for IL-6 reappraisal is coming.

Abbreviations

AMPK: 

monophosphate-activated protein kinase

CAD: 

coronary artery disease

CRP: 

C reactive protein

IL-6: 

interleukin-6

TNFα: 

tumor necrosis factor alpha

T1DM: 

type 1 diabetes mellitus

T2DM: 

type 2 diabetes mellitus.

Declarations

Acknowledgements

This work was supported in part by the Cardiovascular Diabetology Research Foundation (RA 58-040-684-1), Holon, Israel.

Authors’ Affiliations

(1)
Sackler Faculty of Medicine, Tel-Aviv University
(2)
Cardiovascular Diabetology Research Foundation
(3)
Cardiac Rehabilitation Institute, Sheba Medical Center

References

  1. Gerszten RE, Wang TJ: The search for new cardiovascular biomarkers. Nature. 2008, 51: 949-952. 10.1038/nature06802.View ArticleGoogle Scholar
  2. Steinbrich-Zöllner M, Grün JR, Kaiser T, Biesen R, Raba K, Wu P, Thiel A, Rudwaleit M, Sieper J, Burmester GR, Radbruch A, Grützkau A: From transcriptome to cytome: integrating cytometric profiling, multivariate cluster, and prediction analyses for a phenotypical classification of inflammatory diseases. Cytometry A. 2008, 73: 333-340.View ArticlePubMedGoogle Scholar
  3. Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001, 69: 89-95. 10.1067/mcp.2001.113989.View ArticleGoogle Scholar
  4. Azuaje F, Devaux Y, Wagner D: Computational biology for cardiovascular biomarker discovery. Brief Bioinform. 2009, 10: 367-377. 10.1093/bib/bbp008.View ArticlePubMedGoogle Scholar
  5. Fisman EZ, Adler Y, Tenenbaum A: Biomarkers in cardiovascular diabetology: interleukins and matrixins. Adv Cardiol. 2008, 45: 44-64. full_text.View ArticlePubMedGoogle Scholar
  6. Rus HG, Vlaicu R, Niculescu F: Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis. 1996, 127: 263-271. 10.1016/S0021-9150(96)05968-0.View ArticlePubMedGoogle Scholar
  7. Reuben DB, Ferrucci L, Wallace R, Tracy RP, Corti MC, Heimovitz H, Harris TB: The prognostic value of serum albumin in healthy older persons with low and high serum interleukin-6 (IL-6) levels. J Am Geriatr Soc. 2000, 48: 1404-1407.View ArticlePubMedGoogle Scholar
  8. Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, Rebuzzi AG, Ciliberto G, Maseri A: Elevated levels of IL-6 in unstable angina. Circulation. 1996, 94: 874-877.View ArticlePubMedGoogle Scholar
  9. Biasucci LM, Liuzzo G, Grillo RL, Caligiuri G, Rebuzzi AG, Buffon A, Summaria F, Ginnetti F, Fadda G, Maseri A: Elevated levels of C-reactive protein at discharge predicts recurrent instability in patients with unstable angina. Circulation. 1999, 99: 855-860.View ArticlePubMedGoogle Scholar
  10. Biasucci LM, Liuzzo G, Fantuzzi G, Caligiuri G, Rebuzzi AG, Ginnetti F, Dinarello CA, Maseri A: Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999, 99: 2079-2084.View ArticlePubMedGoogle Scholar
  11. Dinh W, Füth R, Nickl W, Krahn T, Ellinghaus P, Scheffold T, Bansemir L, Bufe A, Barroso MC, Lankisch M: Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders. Cardiovasc Diabetol. 2009, 8: 58-10.1186/1475-2840-8-58.PubMed CentralView ArticlePubMedGoogle Scholar
  12. Meléndez GC, McLarty JL, Levick SP, Du Y, Janicki JS, Brower GL: Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 2010, 56: 225-231. 10.1161/HYPERTENSIONAHA.109.148635.PubMed CentralView ArticlePubMedGoogle Scholar
  13. Fisman EZ, Benderly M, Esper RJ, Behar S, Boyko V, Adler Y, Tanne D, Matas Z, Tenenbaum A: Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction. Am J Cardiol. 2006, 98: 14-18. 10.1016/j.amjcard.2006.01.045.View ArticlePubMedGoogle Scholar
  14. Vahtola E, Louhelainen M, Forstén H, Merasto S, Raivio J, Kaheinen P, Kytö V, Tikkanen I, Levijoki J, Mervaala E: Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat. Cardiovasc Diabetol. 2010, 9: 5-10.1186/1475-2840-9-5.PubMed CentralView ArticlePubMedGoogle Scholar
  15. Spranger J, Kroke A, Möhlig 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. 10.2337/diabetes.52.3.812.View ArticlePubMedGoogle Scholar
  16. Snell-Bergeon JK, West NA, Mayer-Davis EJ, Liese AD, Marcovina SM, D'Agostino RB, Hamman RF, Dabelea D: Inflammatory markers are increased in youth with type 1 diabetes: the SEARCH Case-Control study. J Clin Endocrinol Metab. 2010, 95: 2868-2876. 10.1210/jc.2009-1993.PubMed CentralView ArticlePubMedGoogle Scholar
  17. Rachon D, Mysliwska J, Suchecka-Rachon K, Semetkowska-Jurkiewicz B, Zorena K, Lysiak-Szydlowska W: Serum interleukin-6 levels and bone mineral density at the femoral neck in postmenopausal women with type 1 diabetes. Diabet Med. 2003, 20: 475-480. 10.1046/j.1464-5491.2003.00953.x.View ArticlePubMedGoogle Scholar
  18. Tuttolomondo A, La Placa S, Di Raimondo D, Bellia C, Caruso A, Lo Sasso B, Guercio G, Diana G, Ciaccio M, Licata G, Pinto A: Adiponectin, resistin and IL-6 plasma levels in subjects with diabetic foot and possible correlations with clinical variables and cardiovascular co-morbidity. Cardiovasc Diabetol. 2010, 9: 50-10.1186/1475-2840-9-50.PubMed CentralView ArticlePubMedGoogle Scholar
  19. Kitamura A, Hasegawa G, Obayashi H, Kamiuchi K, Ishii M, Yano M, Tanaka T, Yamaguchi M, Shigeta H, Ogata M, Nakamura N, Yoshikawa T: Interleukin-6 polymorphism (-634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes. Diabet Med. 2002, 19: 1000-1005. 10.1046/j.1464-5491.2002.00844.x.View ArticlePubMedGoogle Scholar
  20. Burkhardt K, Schwarz S, Pan C, Stelter F, Kotliar K, Von Eynatten M, Sollinger D, Lanzl I, Heemann U, Baumann M: Myeloid-related protein 8/14 complex describes microcirculatory alterations in patients with type 2 diabetes and nephropathy. Cardiovasc Diabetol. 2009, 8: 10-10.1186/1475-2840-8-10.PubMed CentralView ArticlePubMedGoogle Scholar
  21. Kamimura D, Ishihara K, Hirano T: IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol. 2003, 149: 1-38. full_text.PubMedGoogle Scholar
  22. Andrejko KM, Chen J, Deutschman CS: Intrahepatic STAT-3 activation and acute phase gene expression predict outcome after CLP sepsis in the rat. Am J Physiol. 1998, 275: G1423-G1429.PubMedGoogle Scholar
  23. Fernández-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, Ricart W: Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 2001, 86: 1154-1159. 10.1210/jc.86.3.1154.View ArticlePubMedGoogle Scholar
  24. Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE, Wolf GT, Teknos TN: Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. 2008, 113: 750-757. 10.1002/cncr.23615.View ArticlePubMedGoogle Scholar
  25. Barut B, Chauhan D, Uchiyama H, Anderson KC: Interleukin-6 functions as an intracellular growth factor in hairy cell leukemia in vitro. J Clin Invest. 1993, 92: 2346-2352. 10.1172/JCI116839.PubMed CentralView ArticlePubMedGoogle Scholar
  26. Alokail MS, Al-Daghri NM, Al-Attas OS, Hussain T: Combined effects of obesity and type 2 diabetes contribute to increased breast cancer risk in premenopausal women. Cardiovasc Diabetol. 2009, 8: 33-10.1186/1475-2840-8-33.PubMed CentralView ArticlePubMedGoogle Scholar
  27. Gauldie J, Northemann W, Fey GH: IL-6 functions as an exocrine hormone in inflammation. Hepatocytes undergoing acute phase responses require exogenous IL-6. J Immunol. 1990, 15 (144): 3804-3808.Google Scholar
  28. Peters M, Jacobs S, Ehlers M, Vollmer P, Müllberg J, Wolf E, Brem G, Meyer zum Büschenfelde KH, Rose-John S: The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med. 1996, 183: 1399-1406. 10.1084/jem.183.4.1399.View ArticlePubMedGoogle Scholar
  29. Cuschieri J, Bulger E, Schaeffer V, Sakr S, Nathens AB, Hennessy L, Minei J, Moore EE, O'Keefe G, Sperry J, Remick D, Tompkins R, Maier RV, Inflammation and the Host Response to Injury Collaborative Research Program: Early elevation in random plasma IL-6 after severe injury is associated with development of organ failure. Shock. 2010, 34: 346-351. 10.1097/SHK.0b013e3181d8e687.PubMed CentralView ArticlePubMedGoogle Scholar
  30. Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani A, Gelman S: Raised interleukin-6 levels in obese patients. Obes Res. 2000, 8: 673-675. 10.1038/oby.2000.86.View ArticlePubMedGoogle Scholar
  31. Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, Keaney JF, Meigs JB, Lipinska I, Kathiresan S, Murabito JM, O'Donnell CJ, Benjamin EJ, Fox CS: Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation. 2007, 116: 1234-1241. 10.1161/CIRCULATIONAHA.107.710509.View ArticlePubMedGoogle Scholar
  32. Senn JJ, Klover PJ, Nowak IA, Mooney RA: Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002, 51: 3391-3399. 10.2337/diabetes.51.12.3391.View ArticlePubMedGoogle Scholar
  33. Bastard JP, Maachi M, Van Nhieu JT, Jardel C, Bruckert E, Grimaldi A, Robert JJ, Capeau J, Hainque B: Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002, 87: 2084-2089. 10.1210/jc.87.5.2084.View ArticlePubMedGoogle Scholar
  34. Rotter V, Nagaev I, Smith U: Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-α, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003, 278: 45777-45784. 10.1074/jbc.M301977200.View ArticlePubMedGoogle Scholar
  35. Hung J, McQuillan BM, Chapman CM, Thompson PL, Beilby JP: Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance. Arterioscler Thromb Vasc Biol. 2005, 25: 1268-73. 10.1161/01.ATV.0000163843.70369.12.View ArticlePubMedGoogle Scholar
  36. Trøseid M, Seljeflot I, Arnesen H: The role of interleukin-18 in the metabolic syndrome. Cardiovasc Diabetol. 2010, 9: 11-10.1186/1475-2840-9-11.PubMed CentralView ArticlePubMedGoogle Scholar
  37. Rathcke CN, Vestergaard H: YKL-40--an emerging biomarker in cardiovascular disease and diabetes. Cardiovasc Diabetol. 2009, 8: 61-10.1186/1475-2840-8-61.PubMed CentralView ArticlePubMedGoogle Scholar
  38. Heikkilä K, Ebrahim S, Rumley A, Lowe G, Lawlor DA: Associations of circulating C-reactive protein and interleukin-6 with survival in women with and without cancer: findings from the British Women's Heart and Health Study. Cancer Epidemiol Biomarkers Prev. 2007, 16: 1155-1159. 10.1158/1055-9965.EPI-07-0093.View ArticlePubMedGoogle Scholar
  39. Knudsen EC, Seljeflot I, Michael A, Eritsland J, Mangschau A, Müller C, Arnesen H, Andersen GØ: Increased levels of CRP and MCP-1 are associated with previously unknown abnormal glucose regulation in patients with acute STEMI: a cohort study. Cardiovasc Diabetol. 2010, 9: 47-10.1186/1475-2840-9-47.PubMed CentralView ArticlePubMedGoogle Scholar
  40. Ley SH, Hegele RA, Connelly PW, Harris SB, Mamakeesick M, Cao H, Gittelsohn J, Retnakaran R, Zinman B, Hanley AJ: Assessing the association of the HNF1A G319S variant with C-reactive protein in Aboriginal Canadians: a population-based epidemiological study. Cardiovasc Diabetol. 2010, 9: 39-10.1186/1475-2840-9-39.PubMed CentralView ArticlePubMedGoogle Scholar
  41. Osawa H, Doi Y, Makino H, Ninomiya T, Yonemoto K, Kawamura R, Hata J, Tanizaki Y, Iida M, Kiyohara Y: Diabetes and hypertension markedly increased the risk of ischemic stroke associated with high serum resistin concentration in a general Japanese population: the Hisayama Study. Cardiovasc Diabetol. 2009, 8: 60-10.1186/1475-2840-8-60.PubMed CentralView ArticlePubMedGoogle Scholar
  42. Fisman EZ, Motro M, Tenenbaum A: Cardiovascular diabetology in the core of a novel interleukins classification: the bad, the good and the aloof. Cardiovasc Diabetol. 2003, 2: 11-10.1186/1475-2840-2-11.PubMed CentralView ArticlePubMedGoogle Scholar
  43. Pedersen BK, Febbraio MA: Point: Interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol. 2007, 102: 814-816. 10.1152/japplphysiol.01208.2006.View ArticlePubMedGoogle Scholar
  44. D'Auria L, Bonifati C, Mussi A, D'Agosto G, De Simone C, Giacalone B, Ferraro C, Ameglio F: Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared with healthy subjects and correlate with disease activity. Eur Cytokine Netw. 1997, 8: 383-387.PubMedGoogle Scholar
  45. Yamamura M, Yamada Y, Momita S, Kamihira S, Tomonaga M: Circulating interleukin-6 levels are elevated in adult T-cell leukaemia/lymphoma patients and correlate with adverse clinical features and survival. Br J Haematol. 1998, 100: 129-134. 10.1046/j.1365-2141.1998.00538.x.View ArticlePubMedGoogle Scholar
  46. Mathew M, Tay E, Cusi K: Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovasc Diabetol. 2010, 9: 9-10.1186/1475-2840-9-9.PubMed CentralView ArticlePubMedGoogle Scholar
  47. Febbraio MA, Pedersen BK: Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 2002, 16: 1335-1347. 10.1096/fj.01-0876rev.View ArticlePubMedGoogle Scholar
  48. Angstwurm MW, Gartner R, Ziegler-Heitbrock HW: Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine. 1997, 9: 370-374. 10.1006/cyto.1996.0178.View ArticlePubMedGoogle Scholar
  49. Node K, Inoue T: Postprandial hyperglycemia as an etiological factor in vascular failure. Cardiovasc Diabetol. 2009, 8: 23-10.1186/1475-2840-8-23.PubMed CentralView ArticlePubMedGoogle Scholar
  50. Sakamoto K, Arakawa H, Mita S, Ishiko T, Ikei S, Egami H, Hisano S, Ogawa M: Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine. 1994, 6: 181-186. 10.1016/1043-4666(94)90040-X.View ArticlePubMedGoogle Scholar
  51. Keski-Nisula L, Hirvonen MR, Roponen M, Heinonen S, Pekkanen J: Spontaneous and stimulated interleukin-6 and tumor necrosis factor-alpha production at delivery and three months after birth. Eur Cytokine Netw. 2004, 15: 67-72.PubMedGoogle Scholar
  52. Kitanovski L, Jazbec J, Hojker S, Gubina M, Derganc M: Diagnostic accuracy of procalcitonin and interleukin-6 values for predicting bacteremia and clinical sepsis in febrile neutropenic children with cancer. Eur J Clin Microbiol Infect Dis. 2006, 25: 413-415. 10.1007/s10096-006-0143-x.View ArticlePubMedGoogle Scholar
  53. Tilg H, Dinarello CA, Mier JW: IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today. 1997, 18: 428-432. 10.1016/S0167-5699(97)01103-1.View ArticlePubMedGoogle Scholar
  54. Petersen AM, Pedersen BK: The anti-inflammatory effect of exercise. J Appl Physiol. 2005, 98: 1154-1162. 10.1152/japplphysiol.00164.2004.View ArticlePubMedGoogle Scholar
  55. Bermudez LE, Wu M, Petrofsky M, Young LS: Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in macrophages. Infect Immun. 1992, 60: 4245-4252.PubMed CentralPubMedGoogle Scholar
  56. Mancuso G, Tomasello F, Migliardo M, Delfino D, Cochran J, Cook JA, Teti G: Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease. Infect Immun. 1994, 62: 4997-5002.PubMed CentralPubMedGoogle Scholar
  57. van Vugt H, van Gool L, de Ridder L: Alpha 2 macroglobulin of the rat, and acute phase protein, mitigates the early course of endotoxin shock. Br J Exp Pathol. 1986, 67: 313-319.PubMed CentralPubMedGoogle Scholar
  58. Woloski BM, Smith EM, Meyer WJ, Fuller GM, Blalock JE: Corticotropin-releasing activity of monokines. Science. 1985, 230: 1035-1037. 10.1126/science.2997929.View ArticlePubMedGoogle Scholar
  59. Liu Z, Simpson RJ, Cheers C: Recombinant interleukin-6 protects mice against experimental bacterial infection. Infect Immun. 1992, 60: 4402-4406.PubMed CentralPubMedGoogle Scholar
  60. Steensberg A, Fischer CP, Sacchetti M, Keller C, Osada T, Schjerling P, van Hall G, Febbraio MA, Pedersen BK: Acute interleukin-6 administration does not impair muscle glucose uptake or whole body glucose disposal in healthy humans. J Physiol. 2003, 548: 631-638. 10.1113/jphysiol.2002.032938.PubMed CentralView ArticlePubMedGoogle Scholar
  61. Keller P, Keller C, Carey AL, Jauffred S, Fischer CP, Steensberg A, Pedersen BK: Interleukin-6 production by contracting human skeletal muscle: autocrine regulation by IL-6. Biochem Biophys Res Commun. 2003, 310: 550-554. 10.1016/j.bbrc.2003.09.048.View ArticlePubMedGoogle Scholar
  62. Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, Xiang X, Giralt M, Hidalgo J, Saha AK, Pedersen BK: AMPK activity is diminished in tissues of the IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun. 2004, 320: 449-454. 10.1016/j.bbrc.2004.05.188.View ArticlePubMedGoogle Scholar
  63. Wojtaszewski JF, Jorgensen SB, Frosig C, Macdonald C, Birk JB, Richter EA: Insulin signalling: effects of prior exercise. Acta Physiol Scand. 2003, 178: 321-328. 10.1046/j.1365-201X.2003.01151.x.View ArticlePubMedGoogle Scholar
  64. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA: IL-6 increases insulin stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMPK. Diabetes. 2006, 55: 2688-2697. 10.2337/db05-1404.View ArticlePubMedGoogle Scholar
  65. Richter EA, Mikines KJ, Galbo H, Kiens B: Effect of exercise on insulin action in human skeletal muscle. J Appl Physiol. 1989, 66: 876-885.PubMedGoogle Scholar
  66. Mohr T, Andersen JL, Biering-Sørensen F, Galbo H, Bangsbo J, Wagner A, Kjaer M: Long-term adaptation to electrically induced cycle training in severe spinal cord injured individuals. Spinal Cord. 1997, 35: 1-16. 10.1038/sj.sc.3100343.View ArticlePubMedGoogle Scholar
  67. Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang W-Z, Mori C, Shiota K, Yoshida N, Kishimoto T: Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci. 1996, 93: 407-411. 10.1073/pnas.93.1.407.PubMed CentralView ArticlePubMedGoogle Scholar
  68. Hennigan S, Kavanaugh A: Interleukin-6 inhibitors in the treatment of rheumatoid arthritis. Ther Clin Risk Manag. 2008, 4: 767-775.PubMed CentralPubMedGoogle Scholar
  69. Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T: Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008, 371: 998-1006. 10.1016/S0140-6736(08)60454-7.View ArticlePubMedGoogle Scholar
  70. Petersen AM, Pedersen BK: The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol. 2006, 57 (Suppl 10): 43-51.PubMedGoogle Scholar
  71. Pedersen BK, Fischer CP: Beneficial health effects of exercise--the role of IL-6 as a myokine. Trends Pharmacol Sci. 2007, 28: 152-156. 10.1016/j.tips.2007.02.002.View ArticlePubMedGoogle Scholar
  72. Kristiansen OP, Mandrup-Poulsen T: Interleukin-6 and diabetes: the good, the bad, or the indifferent?. Diabetes. 2005, 54 (Suppl 2): S114-124. 10.2337/diabetes.54.suppl_2.S114.View ArticlePubMedGoogle Scholar
  73. Gadient RA, Otten UH: Interleukin-6 (IL-6) - a molecule with both beneficial and destructive potentials. Prog Neurobiol. 1997, 52: 379-90. 10.1016/S0301-0082(97)00021-X.View ArticlePubMedGoogle Scholar
  74. Stevenson RL: Strange case of Dr Jekyll and Mr Hyde. 2008, Plattsburgh, NY: Tundra Books IncGoogle Scholar

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