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