Interleukin-1 Signaling Pathways in Inflammatory Responses

Interleukin-1 (IL-1) encompasses a family of cytokines, most notably IL-1β, that serve as key mediators of inflammation in both innate and adaptive immunity. Binding of IL-1β to its signalling receptor, IL-1R1, together with the IL-1 receptor accessory protein (IL-1RAcP), triggers recruitment of the adaptor MyD88. This assembly activates downstream kinases including IRAKs and TRAF6, culminating in the concerted activation of transcription factors such as NF-κB and AP-1 and propagation of MAPK and PI3K–AKT pathways. The resultant gene programme drives expression of additional cytokines, chemokines and adhesion molecules that orchestrate leukocyte recruitment and vascular changes. Homeostatic balance is maintained by inhibitory regulators: IL-1R2 acts as a decoy receptor, IL-1R8 (SIGIRR) dampens TIR-domain signalling, and endogenous antagonists such as IL-1Ra compete for receptor binding. Dysregulation underlies pathologies ranging from sepsis and autoimmunity to cancer, making the IL-1 axis a focal point for therapeutic intervention, from receptor antagonists to small-molecule inhibitors.

Research from Nature Portfolio

Recent studies have identified a novel low-molecular-weight antagonist of IL-1β that binds an allosteric site on the mature cytokine, preventing its engagement with IL-1R1. Structure-guided optimisation yielded a compound with single-digit micromolar potency in vitro, validated by X-ray crystallography which revealed conformational changes in two loop regions critical for receptor binding. Cellular assays confirmed blockade of IL-1β-induced signalling in primary human fibroblasts, highlighting a potential oral therapeutic approach that complements existing antibody-based strategies. Complementary structural analyses have also defined transient, excited states of IL-1β that may serve as additional targets for future inhibitor development.

Interleukin-1 Signaling Pathways in Inflammatory Responses publication trend

The graph below shows the total number of articles in interleukin-1 signaling pathways in inflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

Interleukin-1β (IL-1β): Pro-inflammatory cytokine central to innate and adaptive immune activation.

IL-1 receptor type I (IL-1R1): Signalling receptor that associates with IL-1RAcP to initiate downstream cascades.

Decoy receptor (IL-1R2): Non-signalling receptor that sequesters IL-1 without eliciting signal transduction.

MyD88: Adaptor protein recruiting kinases to the IL-1 receptor complex, leading to NF-κB and MAPK activation.

Inflammasome: Multiprotein complex that activates caspase-1 to process pro-IL-1β into its mature form.

References

1. Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β. Nature Communications (2023).
2. SLAMF7 regulates inflammatory response in macrophages during polymicrobial sepsis. Journal of Clinical Investigation (2023).
3. Loss of T follicular regulatory cell-derived IL-1R2 augments germinal centre reactions via increased IL-1. JCI Insight (2024).
4. The Interleukin-1 Receptor Accessory Protein (IL-1RAcP) Is Essential for IL-1-induced Activation of Interleukin-1 Receptor-associated Kinase (IRAK) and Stress-activated Protein Kinases (SAP Kinases)*. Journal of Biological Chemistry (1997).
5. Interleukin (IL) 1β Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-Kinase-dependent AKT/IκB Kinase α Pathway Targeting Activator Protein-1*. Journal of Biological Chemistry (2008).
6. SIGIRR Inhibits Interleukin-1 Receptor- and Toll-like Receptor 4-mediated Signaling through Different Mechanisms*. Journal of Biological Chemistry (2005).