Review ArticleThe varying faces of IL-6: From cardiac protection to cardiac failure
Introduction
IL6 is a pleiotropic cytokine which bridges the innate and adaptive immune systems [1]. Perturbations or dysfunction in the transition from innate to adaptive immunity have long term consequences for inflammation and autoimmunity [2]. The acute response to IL6, which is largely protective, to chronic, long term signaling leading to pathogenic inflammation and autoimmunity is an example of the varying faces of IL6 [3].
IL6 has a wide array of biological functions and is produced by many cells of the body. Originally identified as a B-cell differentiation factor, IL6 is now recognized as a cytokine that regulates many processes such as the acute-phase response, inflammation and hematopoiesis. IL6 can be made by most tissues as well as virtually all cells of the immune system. IL6 can signal either through membrane-bound receptors or, uniquely within the IL-6 family of cytokines, can signal in trans, with a soluble form of its receptor. IL6 has been shown to participate in neurogenesis, wound healing and hepatic regeneration [4], [5], [6]. Acutely, IL6 responds to almost all perturbations of homeostasis. However, when IL6 remains elevated chronically, the protective roles IL6 have maintaining tissue integrity and signaling the immune response, are no longer required and constant signaling becomes associated with fibrosis and chronic inflammation. This dual role of IL6, from acute and beneficial to chronic and harmful, is the subject of this review.
Section snippets
Population based studies
Meta-analysis of human studies has demonstrated that long-term elevation of IL6 levels more than double a person’s life-time risk of coronary heart disease [7]. These studies, among many others, demonstrate an association between pathology and chronic IL6 levels. Recent studies have established a causal role of increased IL6R protein levels in coronary heart disease (CHD) [8], [9], [10]. Not understood is whether elevated IL6 was a byproduct of the cardiovascular disease (CVD) or was serving a
IL6. biological functions and signaling
IL6 is a member of the IL6 family of cytokines that also includes cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF) leukemia inhibitory factor (LIF), neuropoietin (NPN), and oncostatin M [49], [50], [51].
As a multi-functional cytokine, IL6 acts on the immune system as well as other local tissues. Within the immune system, IL6 can direct the development and activation status of both innate and adaptive immune cells. IL6 signaling up-regulates
IL-6 in mouse models of inflammatory disease
IL6 is pathogenic in a variety of inflammatory mouse models. IL6KO mice are resistant to experimentally induced RA [96], colitis [87], experimental autoimmune encephalitis (EAE) [97], experimental autoimmune myocarditis (EAM) [98] and autoimmune kidney disease [99]. Additionally, antibodies that target IL6 signaling block the development of many of these same diseases. IL6R blockade ameliorates colitis [87], inhibits the onset of autoimmune kidney disease [100] and inhibits the development of
IL-6 in the heart
The cellular response to IL6 in the heart has been well characterized. Cardiac tissue provides a revealing example where the duration of signaling, from acute to chronic, demonstrates the protective and pathogenic transition.
IL6 family signaling on cardiac myocytes is cardio protective during the acute response however, when remains elevated chronically, induces maladaptive hypertrophy and decreases contractile function [106], [107]. Myocytes themselves make IL6 in response to injury and in
Conclusions
Classically IL6 is considered to be a proinflammatory cytokine. When homeostasis is disturbed within a host IL6 is elevated and induces protective responses determined by the nature of the insult. IL6 can activate immune cells, direct immune cell trafficking, signal protective responses in local tissue, initiate the acute phase response or contribute to wound healing. In the acute response, these are all vital functions. However, beyond this temporally limited role, the proinflammatory nature
Acknowledgements
This work was supported by the National Institutes of Health/National Heart, Lung and Blood Institute (NIH/NHLBI) Grants R01 HL113008 (to N.R. Rose) and R01HL118183 (D. Čiháková).
References (134)
- et al.
IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation
Trends Immunol
(2003) - et al.
The interleukin-6 pathway and atherosclerosis
Lancet
(2012) - et al.
Identification of a novel regulatory region in the interleukin-6 gene promoter
Cytokine
(2008) - et al.
Serum interleukin 6 levels become elevated in acute myocardial infarction
J Mol Cell Cardiol
(1992) - et al.
Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD)
J Am Coll Cardiol
(1996) - et al.
Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure
J Am Coll Cardiol
(1998) The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases
Biochim Biophys Acta
(2002)Local delivery of soluble interleukin-6 receptors to improve the outcome of alpha-toxin producing Staphylococcus aureus infection in mice
Immunobiology
(2005)- et al.
Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease
Blood
(1989) - et al.
Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy
Blood
(2000)
Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial
Lancet
A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease
Gastroenterology
A possible role for soluble IL-6 receptor in the pathogenesis of systemic onset juvenile chronic arthritis
Cytokine
IL-6 levels in acute and post myocardial infarction: their relation to CRP levels, infarction size, left ventricular systolic function, and heart failure
Eur J Intern Med
Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation
Immunity
Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress
Immunity
Molecular cloning and expression of an IL-6 signal transducer, gp130
Cell
Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130
Cell
CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130
Cell
Interleukin-6 signal transducer gp130 mediates oncostatin M signaling
J Biol Chem
Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex
J Biol Chem
Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor
Cytokine
Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE)
J Biol Chem
TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling
Immunity
Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment
Immunity
Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway
Cell
Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis
Cytokine
Directing transition from innate to acquired immunity: defining a role for IL-6
J Immunol
The interface between innate and adaptive immunity
Nat Immunol
Interleukin 6 and liver regeneration
Gut
Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice
J Leukoc Biol
Interleukin-6, a major cytokine in the central nervous system
Int J Biol Sci.
Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review
PLoS Med
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
Lancet
Effects of genetic variation on chromatin structure and the transcriptional machinery: analysis of the IL6 gene locus
Genes Immun
Association of serum interleukin-6 concentration with a functional IL6-6331T>C polymorphism
Clin Chem
The– 174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families
Arthritis Rheum
Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis
Arthritis Rheum
Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement
Arthritis Res Ther
Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis
New Engl J Med
Interleukin-6 receptor pathways in abdominal aortic aneurysm
Eur Heart J
Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy
JAMA, J Am Med Assoc
Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation
Am J Pathol
Endogenous interleukin-6 plays a crucial protective role in streptococcal toxic shock syndrome via suppression of tumor necrosis factor alpha production
Infect Immun
The soluble interleukin 6 receptor: mechanisms of production and implications in disease
FASEB J: Off Publ Fed Am Soc Exp Biol
Constitutive production of interleukin-6 and immunologic features in cardiac myxomas
Arthritis Rheum
Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis
Eur J Immunol
Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial
Arthritis Rheum
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
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