IL-18: A Dual-Faced Target from Inflammatory Regulation to Autoimmune Disease Research
Author: Senior Product Manager of UA Views：12 
This article focuses on the molecular characteristics and biological functions of IL-18, systematically elaborating its crucial role as a core member of the IL-1 family in inflammation regulation and immune responses, and analyzing its clinical relevance and research progress in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
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IL-18: A Dual-Faced Target from Inflammatory Regulation to Autoimmune Disease Research
Summary
This article systematically elaborates on the molecular characteristics and biological functions of IL-18, highlighting its crucial role as a core member of the IL-1 family in inflammatory regulation and immune responses. It also analyzes its clinical associations and research progress in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
This article systematically elaborates on the molecular characteristics and biological functions of IL-18, highlighting its crucial role as a core member of the IL-1 family in inflammatory regulation and immune responses. It also analyzes its clinical associations and research progress in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
I. Molecular Characteristics and Family Classification of IL-18
Interleukin-18 (IL-18) is an important member of the IL-1 cytokine superfamily, which is divided into three subfamilies—IL-1, IL-18, and IL-36—based on shared receptor or co-receptor binding mechanisms. The IL-18 subfamily includes IL-18 and IL-37, both of which function by binding to the co-receptor IL-1R5 (also known as IL-18Rα). The human IL-18 gene is located on chromosome 11q22.2-q22.3. Its encoded precursor protein consists of 193 amino acid residues with a molecular weight of approximately 24 kDa and lacks a classical signal peptide sequence. Structurally, IL-18 shares high similarity with IL-1β, both adopting a β-trefoil fold topology, a feature that determines their shared receptor signaling complexes.
II. Synthesis and Distribution of pro-IL-18
Due to the absence of a signal peptide, pro-IL-18 cannot be secreted extracellularly via the classical endoplasmic reticulum-Golgi pathway. Pro-IL-18 is constitutively expressed in various tissue cells. Among mesenchymal cells, endothelial cells are a major source of pro-IL-18. In the gastrointestinal tract, epithelial cells throughout the digestive tract express pro-IL-18, reflecting its role in mucosal barrier immunity. In skin tissue, keratinocytes are the primary producers of pro-IL-18. In the central nervous system, both neurons and glial cells synthesize pro-IL-18, suggesting its potential role in neuroinflammation. Additionally, pro-IL-18 is expressed to varying degrees in other tissues such as the liver, kidneys, lungs, and skeletal muscles. Within the immune system, pro-IL-18 can be detected in monocytes, macrophages, and dendritic cells.
III. Activation and Release Mechanisms of IL-18
Pro-IL-18 requires proteolytic processing by caspases to gain biological activity, with caspase-1 (also known as IL-1β-converting enzyme) being the primary mediator of this maturation process. Upon assembly of the inflammasome complex, caspase-1 undergoes autocatalytic activation and cleaves pro-IL-18 at Asp-X sites, releasing mature IL-18 (comprising 157–159 amino acid residues with a molecular weight of ~18 kDa). Other proteases such as granzyme B and proteinase 3 can also cleave pro-IL-18 under certain conditions, indicating the existence of caspase-1-independent alternative activation pathways.
IV. Physiological Functions and Signal Transduction of IL-18
Mature IL-18 initiates signal transduction by binding to the IL-18 receptor α-chain (IL-18Rα), which recruits the IL-18Rβ-chain to form a high-affinity receptor complex. This complex activates the MyD88 and IRAK signaling pathways, ultimately inducing downstream gene expression via NF-κB and MAPK pathways. The synergistic interaction between IL-18 and IL-12 represents one of its most classic functions in immune responses—jointly activating T cells and NK cells to produce large amounts of IFN-γ, driving Th1-type immune responses and enhancing the antiviral and antitumor activities of cytotoxic T cells and NK cells. IL-18 also promotes Th1 cell differentiation while inhibiting Th17 cell differentiation, thereby balancing immune responses. In inflammasome-mediated immune responses, IL-18 plays a vital role in host defense against infections and inflammatory regulation.
V. Clinical Associations Between IL-18 and Autoimmune Diseases
Regarding the association between IL-18 and rheumatoid arthritis (RA), multiple studies have explored the relationship between IL-18 gene polymorphisms and RA susceptibility, but a meta-analysis revealed no consistent link. A clinical trial using IL-18BP for RA treatment was ultimately discontinued. Thus, the role of IL-18 in RA pathogenesis remains unclear. In contrast, clinical studies have shown elevated IL-18 levels in systemic lupus erythematosus (SLE), though no IL-18-targeted drugs have been approved for SLE treatment to date.
VI. Conclusion
As a unique pro-inflammatory cytokine, the signal peptide-free molecular structure of IL-18 dictates its synthesis, processing, and release under multi-layered precise regulation. Its core functions in inducing IFN-γ production and balancing Th1/Th2 immune responses make it indispensable in host defense and immune modulation. Although the clinical relevance of IL-18 in rheumatoid arthritis remains controversial, its elevated expression in systemic lupus erythematosus suggests potential pathological significance in specific autoimmune diseases. Recombinant human IL-18 protein, as a critical tool for basic research and drug development, will continue to facilitate in-depth exploration of IL-18 signaling networks and related therapeutic strategies.
In IL-18-related basic research and drug screening, high-quality recombinant human IL-18 protein is essential for receptor binding assays, cellular functional studies, and signaling pathway analysis. To meet these research needs, U-Share offers IL-18 Protein, Human, suitable for applications such as IL-18/IL-18R binding analysis, T cell and NK cell functional studies, and IL-18 signaling pathway investigation.
This article is reviewed and published by the technical expert team of UA
Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.
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