The IL-1 family of cytokines and receptors in rheumatic diseases

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Abstract

More than any other cytokine family, the 11 members of the IL-1 family are associated with innate immune responses, which occur in acute inflammation and chronic inflammatory conditions such as rheumatic diseases. In many rheumatic diseases, the severity of the condition can result from the balance between the pro-inflammatory and anti-inflammatory members of the IL-1 family. Pro-inflammatory family members (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ) are found in the articular environment during arthritis and often correlate with the degree of inflammation present. IL-1β has emerged as pivotal for promoting inflammation, particularly in autoinflammatory diseases, whereas IL-1α and the IL-36 subfamily are associated with skin diseases. IL-33 regulates T helper 2 (TH2) cell-mediated diseases, in sharp contrast to IL-18, which mainly regulates TH1 cell-mediated responses. The IL-1 family also contains four members that suppress inflammation: two specific receptor antagonists (IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra)), and two members that broadly suppress innate inflammation by non-specifically reducing several cytokines and chemokines (IL-37 and IL-38). In this Review, each of the eleven IL-1 family cytokines and their receptors are discussed, along with their putative roles in rheumatic disease and therapeutic options for targeting or promoting these cytokines.

Key points

  • The IL-1 family of cytokines contains 11 members that either promote inflammation or specifically or non-specifically limit inflammation.

  • The main functions of the IL-1 family are innate immune reactions and inflammation, rather than acquired immunity.

  • IL-1β has emerged as an important cytokine in the pathogenesis of several rheumatic diseases, and can be targeted to treat these diseases and their associated co-morbidities.

  • IL-18 and IL-1β are the main targets for treating macrophage activation syndrome, a dangerous condition that can occur in several rheumatic diseases.

  • The role of the six newer members of the IL-1 family (IL-36α, IL-36β, IL-36γ, IL-36 receptor antagonist, IL-37 and IL-38) in rheumatic diseases is still being investigated.

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Fig. 1: IL-1 cytokine subfamilies and receptors.
Fig. 2: IL-1 receptor signalling.
Fig. 3: Expression, synthesis, processing and release of IL-1β.
Fig. 4: Systemic manifestations of adult-onset Still’s disease.
Fig. 5: IL-1 family members in macrophage activation syndrome.

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Acknowledgements

The work of C.A.D. is supported by NIH Grant AI-15614. C.A.D. thanks P. Libby, A. Rubartelli, J.-M. Dayer, L. A. B. Joosten, M. Netea, M. Donath, T. Mandrup-Poulsen, D. B. Skouras, T. L. Jansen, M. Janssen, G. Cavalli, G. Kaplanski and D. Novick for helpful discussions and for providing information and feedback in the preparation of this manuscript.

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Correspondence to Charles Anthony Dinarello.

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C.A.D. serves as chair of the SAB of Olatec Therapeutics, LLC, which develops the NLRP3 inhibitor OLT1177 (Dapansutrile).

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