IL-18 Signaling Pathway

Introduction to IL-18

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

Immunity and IL-18

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 in Host Defense

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.

IL-18 signaling pathway

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

Balancing with IL-18 BP

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.