Elsevier

Cytokine

Volume 74, Issue 1, July 2015, Pages 62-68
Cytokine

Review Article
The varying faces of IL-6: From cardiac protection to cardiac failure

https://doi.org/10.1016/j.cyto.2014.12.024Get rights and content

Highlights

  • IL6 is cardio protective during acute insult to the myocardium.

  • IL6 transitions to a pathogenic factor when it remains elevated chronically.

  • The transition is associated with specific downstream signaling unique to IL6.

  • Chronic IL6 signaling is associated with heart failure.

  • In myocarditis chronic IL6 signaling contributes to progression to dilated cardiomyopathy.

Abstract

IL6 is a pleiotropic cytokine that is made in response to perturbations in homeostasis. IL6 becomes elevated in the acute response to host injury and can activate immune cells, direct immune cell trafficking, signal protective responses in local tissue, initial the acute phase response or initiate wound healing. In the short term this proinflammatory response is protective and limits host damage. It is when this acute response remains chronically activated that IL6 becomes pathogenic to the host. Chronically elevated IL6 levels lead to chronic inflammation and fibrotic disorders. The heart is a tissue where this temporal regulation of IL6 is very apparent. Studies from myocardial infarction show how short-term IL6 signaling can protect and preserve the heart tissue in response to acute damage, where long term IL6 signaling or an over-production of IL6R protein plays a causal role in cardiovascular disease. Thus, IL6 can be both protective and pathogenic, depending on the kinetics of the host response.

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).

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