Elsevier

Cytokine

Volume 75, Issue 2, October 2015, Pages 280-290
Cytokine

Review article
IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

https://doi.org/10.1016/j.cyto.2015.05.005Get rights and content

Highlights

  • Cytokines of the IL-1 family play an important role in metabolic inflammation.

  • The development of obesity affects IL-1α, IL-1β, IL-1Ra, IL-18, IL-33 and IL-37 activity.

  • IL-1α, IL-1β, IL-1Ra, IL-18, IL-33 and IL-37 alter insulin signaling routes.

  • The IL-1 family of cytokines holds multiple targets to combat metabolic diseases.

Abstract

Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes.

Section snippets

Historical context

Worldwide the incidence of obesity has increased dramatically. In 2013, the global proportion of overweight (defined as a Body Mass Index (BMI) above 25 kg/m2) or obese (BMI above 30 kg/m2) adults was estimated at 37.5% [1]. Obesity is one of the main contributors for the development of insulin resistance, and strongly increases the risk for type 2 diabetes. Inflammatory mediators link obesity to insulin resistance [2]. Obesity itself results in a pro-inflammatory state in metabolic tissues, as

IL-1α, IL-1β and IL-1 Receptor antagonist

IL-1 is a master regulator of innate immune responses by controlling numerous inflammatory processes [32]. 30 Years ago, two distinct forms of IL-1 were cloned [33], [34] and termed IL-1α and IL-1β [35]. Both IL-1α and IL-1β interact with the IL-1 receptor 1 (IL-1R1) and recruit the IL-1 receptor accessory protein (IL-1R3, formerly IL-1RAcP) to induce a downstream signal via several inflammatory kinases, such as Myd88, ERK, JNK and NFκB, leading to transcription of inflammatory, catabolic genes

IL-18

More than 20 years ago IL-18 was identified as gamma interferon (IFN-γ)-inducing factor [91], [92]. IL-18 primarily induces T-helper-1 responses due to the induction of IFNγ in combination with IL-12. However, in the absence of IL-12, there is a role for T-helper-2 [93] and NK-cell maturation, cytokine production and cytotoxicity [92], [94], [95], [96]. Similar to IL-1β, the protein is synthesised as an inactive precursor and requires caspase-1 processing for activation [45]. IL-18 binds to the

IL-33

IL-33 (formerly IL-1F11), one of the novel IL-1 family members was identified in 2005 [128]. It signals through the ST-2 receptor and its co-receptor IL-1 receptor accessory protein (IL-1RAcP). Several isoforms of the ST2 receptor exist, including a transmembrane receptor (ST2L) and a soluble receptor (sST2), which can serve as a decoy receptor for IL-33 [129]. Full length IL-33 is biologically active, but cleavage by protease elastase, cathepsin G or proteinase 3, results in a 10-fold greater

IL-37

IL-37 is a unique member of the IL-1 family (formerly IL-1F7). The cytokine broadly inhibits inflammation by reducing several signaling kinases and augmenting anti-inflammation genes [150]. Since 2010, an increasing number of studies have described the anti-inflammatory actions of this cytokine in models of disease [151]. During acute and chronic inflammation, IL-37 shifts the cytokine balance away from inflammation [151]. IL-37 binds to the IL-18 Receptor alpha chain but recruits the orphan

IL-36α/β/γ, IL-36Ra and IL-38

IL-36 cytokines are new members of the IL-1 family, discovered a decade ago [164], [165], [166], [167], [168], [169] and identified as IL-36α, -β, -γ (formerly IL-1F6, -8, -9) and receptor antagonist IL-36Ra (formerly IL-1F5). IL-36α, -β, -γ activate dendritic cells and polarize T-helper cell responses and play a significant role in the pathogenesis of skin diseases. As all pro-inflammatory IL-36 cytokines signal through the same receptor, they elicit similar effects. Thus, differences between

Conclusion

IL-1 family members are major players in the initiation and regulation of inflammation associated with obesity (Table 1). IL-1β is well recognized for its role in insulin resistance during experimental obesity. Therefore, blocking endogenous IL-1 with IL-1Ra counteracts this effect in experimental settings, but can be extended to treatment of clinical insulin resistance with the known limitations, such as safety. However, reducing IL-1 activity to increase insulin sensitivity in human

Acknowledgements

Ballak is supported by the Interleukin-1 foundation, Stienstra is supported by a Vidi Grant of the Netherlands Organization for Scientific Research (NWO) (016.136.311). Dinarello is supported by NIH (Grant AI-1561), Van Diepen is supported by a Grant of the Dutch Diabetes Research Foundation (2013.81.1674).

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