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IL18

Official Full Name
interleukin 18
Organism
Homo sapiens
GeneID
3606
Background
The protein encoded by this gene is a proinflammatory cytokine of the IL-1 family that is constitutively found as a precursor within the cytoplasm of a variety of cells including macrophages and keratinocytes. The inactive IL-18 precursor is processed to its active form by caspase-1, and is capable of stimulating interferon gamma production, and of regulating both T helper (Th) 1 and Th2 responses. This cytokine has been implicated in the injury of different organs, and in potentially fatal conditions characterized by a cytokine storm. In humans, IL-18 gene is located on chromosome 11. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2020]
Synonyms
IGIF; IL-18; IL-1g; IL1F4;
Bio Chemical Class
Cytokine: interleukin
Protein Sequence
MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
Open
Disease
Adaptive immunity immunodeficiency, Chronic obstructive pulmonary disease, Follicular lymphoma, Malignant haematopoietic neoplasm, Ovarian cancer, Rheumatoid arthritis, Supraventricular tachyarrhythmia, Type 2 diabetes mellitus
Approved Drug
0
Clinical Trial Drug
6 +
Discontinued Drug
1 +

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Detailed Information

Interleukin-18 (IL-18) is a member of the IL-1 cytokine family, a pro-inflammatory cytokine with the ability to induce IFNγ production, playing an important role in inflammation. It primarily participates in epithelial barrier repair and immune responses of Th1 cells and natural killer (NK) cells. IL-18 forms a signaling complex with IL-18 receptor α (Rα) and β (Rβ) chains on the plasma membrane, thereby inducing various inflammatory cytokines.

Expression Distribution of IL-18

IL-18 is primarily expressed in macrophages, with expression also found in granulocytes and Kupffer cells. Additionally, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells.

Structure of IL-18

IL-18 initially exists as an inactive precursor form called pro-IL-18. Unlike many other secreted proteins, it lacks a signal peptide at the N-terminus but has a leader sequence. This precursor form does not possess biological activity and requires cleavage by inflammasome-activated caspases (such as caspase-1). The cleavage occurs at the N-terminus of pro-IL-18, removing its leader peptide sequence and transforming it into a mature form. The mature form of IL-18 features a β-trefoil domain, which is a common characteristic of IL-1 family cytokines. This structure consists of 12 β-strands, forming a unique cloverleaf shape.

Biological Functions of IL-18

IL-18 is a multifunctional cytokine that plays important roles in maintaining immune homeostasis, inducing inflammatory responses, and regulating specific immune cell functions.

Figure 1. Biological Functions of IL-18. (Shimizu M, et al., 2022)

Promotion of IFNγ Production: IL-18 signals through a heterodimeric cell surface receptor composed of IL-18 receptor (IL-18R) α and β chains (encoded by IL18R1 and IL18RAP, respectively). Receptor binding leads to autophosphorylation of TIR domains, recruiting adaptor proteins TRAM and MYD88, activating MAPK and NF-κB pathways, and inducing the production of other cytokines such as IFNγ. IFN-γ can alter immune cell activity and promote immune responses against pathogens.

Regulation of NK Cell Activity: IL-18 can enhance NK cell cytotoxicity and IFN-γ production, improving their ability to kill tumor cells and virus-infected cells.

Maintenance of Immune Homeostasis: IL-18 can inhibit its activity by binding to IL-18 binding protein (IL-18BP), thereby maintaining immune homeostasis. IL-18BP is a high-affinity "decoy receptor" that can neutralize most circulating IL-18, keeping it biologically inactive. This strong interaction prevents excessive activation of IL-18, thus maintaining immune balance.

Dual Role in Tumors: IL-18 can promote CD8+ T cell exhaustion, while also potentially preventing and delaying exhaustion by enhancing T cell effector functions, increasing its anti-tumor activity.

Role in T Lymphocyte Activation: IL-18 works synergistically with IL-12 to enhance the differentiation of CD4+ T cells into Th1 cells, which produce large amounts of IFN-γ, contributing to cell-mediated immune responses and anti-infection defense. In certain circumstances, IL-18 may promote Th2 cell responses, which produce IL-4, IL-5, and IL-13, contributing to humoral immunity and anti-helminth immune responses. IL-18 works synergistically with other cytokines such as IL-23 to promote the differentiation of CD4+ T cells into Th17 cells, which play a role in inflammation and autoimmune diseases.

Clinical Value of IL-18

IL-18 as a Biomarker: IL-18 is a highly specific biomarker that can be used to diagnose certain autoinflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA) and PSTPIP1-associated diseases, which are referred to as "IL-18 diseases." In sJIA and other autoinflammatory diseases, a significant increase in IL-18 levels may predict the development of macrophage activation syndrome (MAS).

IL-18 and Diseases: IL-18 is associated with various diseases, including autoinflammatory diseases such as Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome; autoimmune diseases; inflammatory bowel disease (IBD); and tumor development. In chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus, IL-18 levels are typically elevated, promoting disease progression.

Targeted Therapy of IL-18

Due to the critical role of IL-18 in various pathological processes, it has become a potential target for therapeutic intervention. Promising approaches include blocking its activation and/or release, mimicking IL-18BP, neutralizing free IL-18, blocking IL-18R, or blocking downstream effector cytokines (such as IFNγ). Currently, multiple antibody drugs targeting IL-18 are in clinical development.

Tadekinig alfa is a recombinant human interleukin-18 binding protein (r-hIL18BP) with high affinity for IL-18. In patients with certain inflammatory diseases, the IL-18/IL-18BP balance is disrupted, leading to elevated levels of free and active IL-18, resulting in pathological inflammation. AB2 Bio's exogenous recombinant human IL-18BP can restore the IL-18/IL-18BP balance, clearing free IL-18, thereby reducing inflammatory responses. Its efficacy is currently being studied for various diseases, including adult-onset Still's disease, lymphoproliferative disorders, immune system diseases, and macrophage activation syndrome.

MAS-825 is a bispecific IL-1β/IL-18 monoclonal antibody developed by Novartis AG for treating coronary artery disease, infant enterocolitis, autoinflammation, hidradenitis suppurativa, and other diseases. It is currently in phase 2 clinical trials.

References

  1. Landy E, Carol H, Ring A, et al. Biological and clinical roles of IL-18 in inflammatory diseases. Nat Rev Rheumatol. 2024 Jan;20(1):33-47.
  2. Clancy DM, Andries J, et al. The pros and confs of IL-18 activation. Immunity. 2024 Jul 9;57(7):1445-1448.
  3. Shimizu M, Takei S, Mori M, Yachie A. Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases. Front Immunol. 2022 Sep 22;13:951535.
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