This website uses cookies to ensure you get the best experience on our website.
- Table of Contents
Interleukin 18 (IL-18) is a pleiotropic cytokine involved in the regulation of innate and acquired immune response. It plays a significant role in the inflammatory response, and is proved to be a suitable diagnostic marker for various disorders.
Interleukin 18 (IL-18) is a proinflammatory cytokine involved in the regulation of innate and acquired immune response. It has a molecular weight of 18-kDa and is mainly produced by activated macrophages and Kupffer cells and can promote IFN-γ production. In addition to these IL-18 producing cells, pro-IL-18 is produced by a wide variety of other cells, including keratinocytes, intestinal epithelial cells, and osteoblasts suggesting it has an important pathophysiological role in health and disease
Reference: Kaplanski, G. Interleukin-18: Biological properties and role in disease pathogenesis. Immunol Rev. 2018; 281: 138– 153. https://doi.org/10.1111/imr.12616
IL- 18 gene is located on chromosome 11 in humans and chromosome 9 in mice whose gene contains 7 exons with two distinct promoters on exon 1 and 2 including an interferon consensus sequence binding protein and a PU.1 binding sites.
IL-18 is a cytokine that stimulates various cell types and has pleiotropic functions. It is a member of the IL-1 family of cytokines and demonstrates a unique function by binding to a specific receptor expressed on various types of cells. By stimulating Th1 cells, and triggering the production of IL-13 and IFN-γ IL-18 plays an important role in the stimulation of B cell proliferation and immunoglobulin production. IL-18 also acts on basophils and mast cells to cause complex physiological reactions such as an allergic response.
Elevated serum levels of IL-18 are reported to correlate with the carcinogenesis of several cancers including breast cancer, lung cancer, gastrointestinal carcinoma, and skin cancer. This cytokine also plays an effector and regulatory role in a variety of early inflammatory responses and is expressed at the sites of chronic inflammation, in autoimmune diseases, and in the context of numerous infectious diseases.
Reference: Wawrocki S, Druszczynska M, Kowalewicz-Kulbat M, Rudnicka W. Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol. 2016;63(1):59-63. doi: 10.18388/abp.2015_1153. Epub 2016 Feb 17. PMID: 26885772.
IL-18 plays an important role in host defense against various infectious microorganisms because it strongly enhances the induction of IFN-γ, nitric oxide (NO), and ROS in phagocytes. In addition, IL-18 directly activates CD8+ T cells, which play a central role in viral clearance. Furthermore, because IL-18 activates Th2 cytokine production and granulocytes in the absence of IL-12, it also acts defensively in helminth infection.
Reference: Nakanishi, Kenji & Tsutsui, Hiroko. (2019). Interleukin-18 in Health and Disease. International Journal of Molecular Sciences. 20. 649. 10.3390/ijms20030649.
Following the trimerization of IL-18/IL-18Rα/IL-18Rβ, MyD88 binds to the Toll-IL-1 receptor (TIR) domain of IL-18Rα and IL-18Rβ. IRAK1 and IRAK4 are combined via the death domain of MyD88 to form a Myddosome. Furthermore, following binding to TRAF6, inhibitor of κB (IκB) is degraded, and phosphorylated p65/p50 NF-κB translocates into the nucleus. The MAPK cascade of Extracellular Signal-regulated Kinase (ERK), c-jun N-terminal kinase (JNK), and p38 is also activated. These signals induce IFN-γ production in Th1 cells and promote cell proliferation. IL-18 stimulation also induces the phosphorylation and activation of phosphatidylinositol-3 kinase (PI3K)/Akt/S6 and mammalian target of rapamycin (mTOR), as well as autophagosome formation and the expressions of Bcl-xL and Bcl2. Although PI3K suppresses inflammatory cytokine production by TLR signaling in myeloid cells this signal enhances the proliferation and survival of NK cells. The PI3K/Akt pathway is also important for the survival of non-immune system cells, such as keratinocytes and neurons following IL-18 stimulation
The proinflammatory activity of IL-18 is balanced by a constitutively secreted IL-18 binding protein (IL18BP) with an extremely high affinity to IL-18, which is significantly higher than that of IL-18Ra. By binding IL-18, IL-18BP diminishes the production of IFN-gamma and other proinflammatory cytokines in order to reduce triggering autoimmune responses to infections.
In humans, an increase in disease severity can be associated with an imbalance between IL-18 and IL-18BP, which yields to elevation of the levels of free IL-18 in the circulation. The increase in the levels of IL-18 and/or IL18BP has been implicated in severity of systemic juvenile idiopathic arthritis, systemic lupus erythematous, myocardial infarction, Crohn’s disease, acute kidney injury, inflammatory bowel disease, sepsis and other diseases.
Reference: Nakanishi, Kenji & Tsutsui, Hiroko. (2019). Interleukin-18 in Health and Disease. International Journal of Molecular Sciences. 20. 649. 10.3390/ijms20030649.
IL-18 also participates in chronic hepatic inflammation, leading to carcinogenesis. It was reported that the serum level of IL-18 is a useful biological marker of tumor invasiveness and an independent prognostic factor for survival among patients with Hepatocellular carcinoma (HCC). Studies have shown that the he serum level of IL-18 is increased in patients with HCV-related stage IV HCC compared with patients with earlier-stage HCC.
The broad spectrum of IL-18 functions, as well as the differing levels of the cytokine and IL-18BP that occur in numerous diseases, indicate that both, IL-18 and IL-18BP, can also be useful as the biomarkers in diagnostics.
Click the pathway map to the right to see pathway details! IL-6 Receptor Pathway Interleukin 6 receptor (also known as CD126) is encoded by the IL6R gene in humans. IL-18 Signaling Pathway IL-18 is a proinflammatory cytokine that belongs to the IL-1 ...
See MoreTroubleshooting guides Cytokine Network Pathway Cytokines are a large category of signaling molecules (~5–20 kDa) acting as immunomodulating agents for autocrine signaling, paracrine signaling, and endocrine signaling. These small proteins are prod...
See MoreTroubleshooting guides Allergic Response Pathway Allergies are when the body's immune system has a hypersensitive reaction towards innocuous substances called allergens. The antigen-presenting cell (APC) complexed with MHC II captures, processes, a...
See MoreAKT Signaling Pathway The Akt/PKB Signaling Pathway is activated by extracellular signals, most commonly a type of growth factor, that phosphorylates PI3K, leading to the production of PIP3. When Akt is completely activated, it is capable of inhibiti...
See MoreIf you would like another pathway to be designed in poster format, contact [email protected] and we will consider the popular signaling pathways for future poster printing. Troubleshooting guides Cell Signaling Pathways Boster is now offering 12"...
See More