Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven agonistic ligands (IL-1a and IL-1β, IL-18, IL-33, IL-36A, and IL-36T), three receptor antagonists (IL-1RA, IL-36RA, and IL-38), and one anti-inflammatory cytokine (IL-37). The IL-1 receptor (IL-1R) family includes ten structurally related receptor molecules (according to the current nomenclature, IL-1R1-10) and a distantly related soluble ILL-18 binding protein (BP), which has been identified as an inhibitor of ILL-18. Tight regulation between ligands and receptors ensures a balance between enhanced innate immunity and uncontrolled inflammation.
(Data source: Green EA, et al. Int J Mol Sci. 2023)
In this article, we focus on IL-1β, as it is the most potent proinflammatory cytokine that, along with IL-1α, binds to IL-1R1, and their signaling initiates multiple pathways associated with different pathological conditions.
Structure of IL-1β:
IL-1β consists of two parts, the N-terminal leader peptide and the C-terminal mature functional domain. Its biological activity is strictly controlled and requires protease treatment to generate an active secretory form.
(Data source: Uniprot)
IL-1β regulation:
IL-1β is mainly secreted by monocytes, macrophages and dendritic cells: (1) First, pathogen-associated molecules DAMPS /PAMPS bind to Toll-like receptors TLRs on monocytes, (2) Activates downstream transcription factors, inducing the transcription of pro- IL-1β and its release into the cytoplasm. (3) In monocytes, TLR signaling also induces the formation of inflammasomes, which activate caspase-1, which in turn cleaves IL -1β, thereby converting it to its mature, bioactive form. (4) Active IL-1β activates the IL-1R1:IL-1R3 receptor complex, thereby exerting multiple, primarily pro-inflammatory, effects, including inducing the transcription of chemokines that promote immune cell recruitment and the transcription of cytokines that promote inflammation. (5-7) At the same time, proinflammatory mediators, including IL-1β itself, increase the production of IL-1Ra. (8) IL-1Ra is released and competitively inhibits the binding of IL-1 to IL-1R1.
(Data source: Green EA, et al. Int J Mol Sci. 2023)
IL-1β-related diseases:
IL-1β is an intrinsic oxidative damage-promoting mechanism in chronic inflammation. Its overexpression is accompanied by massive recruitment of inflammatory cells and expression of proinflammatory cytokines, regulating the complex tissue microenvironment during the common process of tumor cell progression and cancer metastasis.
(Data source: Muthupalani S, et al. Sci Rep. 2023)
Summary:
Clinical studies have demonstrated the pathogenic role of IL-1β in tumor development and its clinical significance: elevated IL-1β levels in the blood and its expression in tumor tissue are associated with poor prognosis, resistance to anticancer drugs (cytostatics, immunotherapy) , and low survival rates. IL-1β inhibitors can help reduce tumor volume and increase response to cancer treatment. Currently, three IL-1β blocking drugs (canakinumab, gevokizumab, and rilonacept) have been approved.
(Data source: Muthupalani S, et al. Sci Rep. 2023)
