Understanding Interleukin-18
Interleukin-18, also known as IL-18 or interferon-gamma-inducing factor (IGIF), belongs to the IL-1 superfamily. It was initially identified as a factor capable of inducing interferon-gamma (IFN-γ) production, thereby connecting the innate and adaptive immune responses. IL-18 is synthesized as an inactive precursor and requires cleavage by caspase-1 to become biologically active.
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Fig. 1 Schematic model of the IL-18 signaling pathways and biological functions. (Wang X, et al., 2023)
The IL-18 Receptor
The actions of IL-18 are mediated through its interaction with a specific cell surface receptor, aptly named the IL-18 receptor (IL-18R). The IL-18R is a heterodimer composed of two subunits: IL-18Rα and IL-18Rβ. IL-18Rα is the ligand-binding subunit, while IL-18Rβ serves as the accessory chain involved in signal transduction.
Upon binding of IL-18 to its receptor, a conformational change occurs, leading to the recruitment of IL-18Rβ to form a high-affinity complex. This complex is crucial for the initiation of downstream signaling events, ultimately influencing cellular responses and immune regulation.
IL-18 Signaling Cascade
The IL-18 signaling cascade is a well-orchestrated series of events that transmit the cytokine's signal from the extracellular environment to the intracellular machinery. The binding of IL-18 to its receptor activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, a pivotal signaling pathway in immune regulation.
Upon receptor engagement, JAKs are recruited to the cytoplasmic domain of IL-18Rβ, leading to their activation. Activated JAKs, in turn, phosphorylate the cytoplasmic tail of IL-18Rβ, creating docking sites for STAT proteins. Subsequently, STAT proteins are recruited and phosphorylated by JAKs, forming homo- or heterodimers that translocate into the nucleus. In the nucleus, STAT dimers act as transcription factors, modulating gene expression and influencing cellular responses.
The IL-18 signaling cascade is not limited to the JAK-STAT pathway; it also involves other signaling molecules, including mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). These pathways collectively contribute to the diverse cellular responses induced by IL-18, ranging from inflammatory cytokine production to cell proliferation and differentiation.
IL-18 Binding Protein
To fine-tune the effects of IL-18 and prevent excessive immune activation, the body employs a regulatory mechanism through the production of the IL-18 binding protein (IL-18BP). IL-18BP is a soluble receptor that competes with cell-bound IL-18R for IL-18 binding, effectively neutralizing the cytokine.
IL-18BP acts as a decoy receptor, sequestering IL-18 and preventing its interaction with the cell surface receptors. This competitive inhibition ensures that IL-18 signaling is tightly regulated, avoiding uncontrolled immune responses that could lead to autoimmune diseases or chronic inflammation.
Clinical Implications and Therapeutic Potential
Given its pivotal role in immune regulation, IL-18 has garnered attention as a potential therapeutic target for various diseases. Aberrant IL-18 signaling has been implicated in conditions such as inflammatory bowel disease (IBD), rheumatoid arthritis, and certain infectious diseases. In IBD, for example, elevated levels of IL-18 have been observed in affected tissues, contributing to the chronic inflammatory process. Targeting IL-18 or its receptors may offer a promising avenue for therapeutic intervention in these conditions. Additionally, the IL-18 signaling cascade has been investigated in the context of cancer. The cytokine's ability to modulate immune responses and influence the tumor microenvironment highlights its potential as a target for immunotherapy strategies.
As our understanding of IL-18 continues to deepen, so does the potential for targeted therapeutic interventions. Harnessing the intricate mechanisms of IL-18 signaling may pave the way for novel treatments in immune-related disorders, offering hope for improved outcomes and quality of life for patients grappling with these conditions.
Reference
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Wang X, Wang L, Wen X, Zhang L, Jiang X, He G. Interleukin-18 and IL-18BP in inflammatory dermatological diseases. Front Immunol. 2023, 14:955369.
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