Interleukin‐1

Abstract

The interleukin‐1 (IL‐1) family of ligands and receptors plays a central role in the generation and regulation of inflammation as a part of the immune response. IL‐1 molecules are best known as members of the pro‐inflammatory protein family called cytokines. They have been shown to play a role, not only during inflammation, but also in influencing additional physiological and pathological functions such as auto‐immune diseases, malignancies and many others. Moreover, the biological balance between pro‐inflammatory and inhibitory activities is crucial, since any shift in IL‐1 family expression has the potential to cause disease.

Key Concepts

  • Interleukin‐1 proteins play a central role in the generation and regulation of inflammatory processes.
  • The IL‐1α and IL1‐β ligands are pro‐inflammatory cytokines. IL‐1Ra and IL‐1RII are natural inhibitors of IL‐1 signalling.
  • Shifts in the balance between agonistic and antagonistic signals of IL‐1 family members are crucial for a proper immune response.
  • Changes in production and secretion of IL‐1 proteins, which determine the balance between activating and neutralising IL‐1R signalling, are widely associated with many human diseases.
  • IL‐1 neutralisation is now considered as an attractive therapeutic strategy for many diseases, including cancer.

Keywords: interleukin‐1; cytokines; inflammation; immune response; IL‐1α; IL‐1β; IL‐1 receptor antagonist; IL‐1 receptor

Figure 1. The Interleukin‐1 gene cluster. Representation of the human chromosome‐2 locus containing the IL‐1 gene cluster showing the relative positions of the known IL‐1 and IL‐1R genes within the IL‐1 gene cluster.
Figure 2. IL‐1 schematic illustration of IL‐1 pro‐inflammatory signalling. IL‐1 cytokines can be proteolytically cleaved. Already active preIL‐1α cleave to mIL‐1α by calpain while nonactive preIL‐1β processed to mIL‐1β by caspase‐1 activated by inflammasome. Intracellular preIL‐1α contains NLS and has nuclear function whereas extracellular preIL‐1α, IL‐1α and IL‐1β induce pro‐inflammatory signalling by binding to IL‐1RI coupled with IL‐1RAcP which further recruit pro‐inflammatory downstream proteins such as MyD88, IRAKs and TRAF6 to induce nuclear transcription factors such as NfκB to induce the translation of further pro‐inflammatory factors.
Figure 3. The Family of IL‐1 receptors, structure–function signalling and interactions with IL‐1 molecules. IL‐1Ra binding to the membrane‐bound IL1RI. bind IL‐1α/β and associates with IL‐1RAcP to transmit a signal. IL‐1Ra binds IL‐1RI but does not allow the recruitment of IL‐1RAcP. IL‐1RII bind IL‐1α/β but lack the cytoplasmic segment, it also competes with IL‐1RI for IL‐1RAcP. Soluble IL‐1RII with or without soluble IL‐1RAcP bind IL‐1α/β and prevent it binding to IL‐1RI. Intracellular cytosolic IL‐1RII interacts with prec‐IL‐1α and prevents its signalling during necrosis.
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Further Reading

Cohen I (2017) DNA damage talks to inflammation. Cytokine & Growth Factor Reviews 33: 35–39. DOI: 10.1016/j.cytogfr.2016.11.002.

Boraschi D and Tagliabue A (2006) The interleukin‐1 receptor family. Vitamins and Hormones 74: 229–254. DOI: 10.1016/S0083-6729(06)74009-2.

Chan JK, Roth J, Oppenheim JJ, et al. (2012) Alarmins: awaiting a clinical response. The Journal of Clinical Investigation 122 (8): 2711–2719. DOI: 10.1172/JCI62423.

Chen GY and Nuñez G (2010) Sterile inflammation: sensing and reacting to damage. Nature Reviews. Immunology 10 (12): 826–837. DOI: 10.1038/nri2873.

Dinarello CA (2009) Immunological and inflammatory functions of the interleukin‐1 family. Annual Review of Immunology 27 (1): 519–550. DOI: 10.1146/annurev.immunol.021908.132612.

Dower SK, Sims JE, Cerretti DP and Bird TA (1992) The interleukin‐1 system: receptors, ligands and signals. Chemical Immunology 51: 33–64. http://www.ncbi.nlm.nih.gov/pubmed/1533129 (accessed 14 September 2018).

Khazim K, Azulay EE, Kristal B and Cohen I (2018) Interleukin 1 gene polymorphism and susceptibility to disease. Immunological Reviews 281 (1): 40–56. DOI: 10.1111/imr.12620.

O'Neill LAJ (2008) The interleukin‐1 receptor/Toll‐like receptor superfamily: 10 years of progress. Immunological Reviews 226 (1): 10–18. DOI: 10.1111/j.1600-065X.2008.00701.x.

Rider P, Voronov E, Dinarello CA, Apte RN and Cohen I (2017) Alarmins: feel the stress. The Journal of Immunology 198 (4): 1395–1402. DOI: 10.4049/jimmunol.1601342.

Sims JE and Smith DE (2010) The IL‐1 family: regulators of immunity. Nature Reviews Immunology 10 (2): 117. DOI: 10.1038/nri2691.

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Etti, Azulay E, Assy, Nimer, and Idan, Cohen(Nov 2018) Interleukin‐1. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028193]