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  • Review Article
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Interleukin-1 function and role in rheumatic disease

Key Points

  • The interleukin (IL)-1 family has 11 members, including the proinflammatory proteins IL-1α and IL-1β, as well the anti-inflammatory IL-1 receptor antagonist

  • Active IL-1β is produced by cleavage of pro-IL-1β by inflammasome-mediated caspase-1 or neutrophil proteases

  • IL-1α is produced and accumulated in the cell and is released upon cell necrosis, thereby serving as an 'alarmin'

  • In addition to mediating acute inflammatory responses, IL-1α and IL-1β link innate and adaptive immunity, facilitating the differentiation of IL-17-producing T cells and innate immune cells

  • Therapeutic inhibition of IL-1 is highly effective in rare autoinflammatory syndromes, but also in more prevalent diseases involving the inflammasome and neutrophil activation such as crystal-induced arthropathies

Abstract

Interleukin (IL)-1, first described 35 years ago as a secreted product of monocytes and neutrophils, refers to IL-1α and IL-1β, two key cytokines in the activation of innate immunity. These cytokines were among the first proteins identified as orchestrators of leukocyte communication, creating the class of secreted products now known as interleukins. The IL-1 family comprises a total of 11 members, including the two activating cytokines IL-1α and IL-1β as well as an inhibitory mediator, the IL-1 receptor antagonist. IL-1 is processed and activated by a caspase-1 dependent mechanism in conjunction with inflammasome assembly, as well as by caspase-1 independent processes that involve neutrophil proteases. Once activated, IL-1α and IL-1β act as potent proinflammatory cytokines at the local level, triggering vasodilatation and attracting monocytes and neutrophils to sites of tissue damage and stress. Importantly, these cytokines are crucial for the induction of matrix enzymes and serve as potent mediators of tissue damage by altering cartilage and bone homeostasis. Systemically, IL-1 cytokines foster the hypothalamic fever response and promote hyperalgesia. Uncontrolled IL-1 activation is a central component of some inflammatory diseases, including rare hereditary syndromes with mutations in inflammasome-associated genes or more frequent diseases such as gout, characterized by neutrophil infiltration and IL-1 activation. Apart from these connections to inflammatory diseases, an important role for IL-1 in inflammatory atherogenesis is also predicted. To date, four potent inhibitors of IL-1 are available for clinical use or in late-stage clinical development, which not only constitute efficacious therapies, but also helped improve our understanding of the role of IL-1 in human disease.

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Figure 1: Activation and signalling of IL-1.
Figure 2: Main functions of IL-1.
Figure 3: Strategies to achieve therapeutic inhibition of IL-1.

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Schett, G., Dayer, JM. & Manger, B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol 12, 14–24 (2016). https://doi.org/10.1038/nrrheum.2016.166

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