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IL-1 pathways in inflammation and human diseases

Nature Reviews Rheumatology volume 6, pages 232–241 (2010)Cite this article

Subjects

Abstract

Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1α and IL-1β, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1β processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases.

Key Points

  • Interleukin (IL)-1, which includes IL-1α and IL-1β, exerts strong proinflammatory activities and has a major role in host responses to exogenous and endogenous noxious stimuli

  • The proinflammatory activities of IL-1 are controlled by several endogenous inhibitors, such as IL-1 receptor antagonist (IL-1Ra), membrane-bound and soluble IL-1 receptor type II and IL-1 receptor accessory protein

  • Numerous exogenous (for example, microbial components and asbestos) and endogenous (for example, monosodium urate and calcium pyrophosphate dihydrate crystals) agents can activate caspase 1, which induces release of bioactive IL-1β

  • The role of IL-1 in disease is exemplified by the description of hereditary autoinflammatory diseases caused by excessive IL-1 signaling secondary to either IL-1β overproduction or IL-1Ra deficiency

  • A beneficial effect of targeting IL-1 has been described in several hereditary and non-hereditary autoinflammatory diseases

  • The potential role of IL-1 in the pathogenesis of type 2 diabetes and smoldering myeloma has been supported by the results of recent clinical trials

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Figure 1: Synthesis, maturation and cellular localization of IL-1α and IL-1β.
Figure 2: Regulation of IL-1 activity by both membrane-bound and soluble forms of IL-1 receptors.
Figure 3: Therapeutic approaches to targeting IL-1.

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Acknowledgements

This work is supported by the Swiss National science Foundation grants 320000-119728 (to C. Gabay) and 320000-12031 (to G. Palmer), and by the Rheumasearch Foundation.

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  1. Division of Rheumatology, University Hospitals of Geneva & Department of Pathology-Immunology, University of Geneva School of Medicine, 26 Avenue Beau-Séjour, 1211, Geneva 14, Switzerland

    Cem Gabay, Céline Lamacchia & Gaby Palmer

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  1. Cem Gabay
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Correspondence to Cem Gabay.

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Gabay, C., Lamacchia, C. & Palmer, G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 6, 232–241 (2010). https://doi.org/10.1038/nrrheum.2010.4

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