Interleukin-18 (IL-18): The Sentinel and Dual Regulator of Inflammatory Response

Interleukin-18 (IL-18) is a member of the interleukin-1 (IL-1) cytokine family and serves as a critical mediator bridging innate and adaptive immunity, particularly renowned for its potent induction of interferon-γ (IFN-γ). Unlike cytokines primarily involved in lymphocyte development or differentiation, IL-18 does not directly induce cell differentiation but functions as a pivotal "co-stimulatory signal" and "amplifier." In synergy with factors such as IL-12 or IL-15, it dramatically enhances type I immune responses. IL-18 plays a key role in defending against viral infections and anti-tumor immunity, but its dysregulation directly drives various autoinflammatory and autoimmune diseases.

IL-18 is primarily constitutively expressed by myeloid cells such as monocytes/macrophages, dendritic cells, and Kupffer cells. Its uniqueness lies in its storage as an inactive precursor (pro-IL-18) in the cytoplasm, with its maturation and release tightly regulated, making it a rapid "sentinel alarm" for the body to respond to dangers.

Unique proteolytic maturation process: The activation of pro-IL-18 depends on inflammasome-mediated proteolytic cleavage. When cells detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) via pattern recognition receptors (e.g., NLRP3), they assemble the inflammasome complex, thereby activating caspase-1. Activated caspase-1 cleaves pro-IL-18 into biologically active mature IL-18 (~18 kDa) and promotes its release into the extracellular space.

IL-18 exerts its effects through its specific receptor (IL-18R), and the expression pattern of this receptor determines its target cell range.

High-affinity receptor (αβ heterodimer): IL-18R consists of the ligand-binding chain IL-18Rα (CD218a) and the signal-transducing chain IL-18Rβ (CD218b). IL-18 first binds to the widely expressed IL-18Rα, forming a low-affinity complex, which then recruits IL-18Rβ to form a high-affinity signaling complex.

Pre-activation dependency of target cells: IL-18Rβ is expressed at low levels on naïve T cells and NK cells. These cells require pre-activation by other signals (e.g., IL-12, IL-15, or antigens) to significantly upregulate IL-18Rβ expression, thereby gaining high responsiveness to IL-18. This characteristic precisely targets IL-18's effects to effector cells already alerted by danger signals.

The core function of IL-18 is to act as a "co-stimulatory factor" and "effector amplifier," with mild effects on its own but explosive effects in the presence of synergistic signals.

Powerful synergistic effect: IL-18 alone induces only low levels of IFN-γ. However, when combined with IL-12, the two produce a potent synergy, inducing extremely high levels of IFN-γ in T cells and NK cells, far exceeding the sum of their individual effects. This is a key mechanism for the rapid establishment of robust Th1-type cellular immunity in response to intracellular pathogens (e.g., Listeria).

Mechanistic basis: IL-12 upregulates IL-18Rβ expression via STAT4, sensitizing cells to IL-18, while IL-18 signaling synergizes with IL-12's STAT4 pathway through NF-κB and other pathways to maximize IFN-γ production at transcriptional and post-transcriptional levels.

IFN-γ-independent activation: Even in the absence of IFN-γ, IL-18 can directly enhance granzyme B expression and cytotoxic function in NK cells and memory CD8⁺ T cells, promoting their direct killing of target cells.

Aiding Th1 polarization: In the presence of antigens, IL-18 can promote naïve CD4⁺ T cell differentiation toward Th1 and enhance the effector function and survival of already differentiated Th1 cells.

In the absence of IL-12, IL-18 can synergize with IL-23 to promote IL-17 and IL-22 production by γδ T cells and macrophages, thereby participating in certain neutrophil-dominated inflammatory or barrier defense responses.

Upon binding to its receptor, IL-18 primarily activates the following inflammation-related pathways, with signaling patterns highly similar to those of the IL-1 family.

MyD88-dependent NF-κB and MAPK pathways (core pathways):

Critical role of the adaptor protein MyD88: The intracellular domain of IL-18R contains a Toll/IL-1 receptor (TIR) domain, which recruits the adaptor protein MyD88. MyD88 then recruits and activates IL-1 receptor-associated kinase (IRAK) family members, triggering downstream signaling cascades.

NF-κB activation: Through the canonical pathway, the activated IKK complex phosphorylates and degrades IκB, releasing NF-κB (p65/p50) into the nucleus to initiate transcription of numerous pro-inflammatory factors (e.g., IL-6, TNF-α) and chemokine genes.

MAPK pathway activation: Simultaneously activates p38, JNK, and ERK MAPK pathways, involved in regulating cellular stress, proliferation, and differentiation.

Crosstalk with other pathways:

Synergizes with the IL-12-induced STAT4 pathway at gene regulatory elements to collectively maximize transcription of genes such as IFN-γ. This "dialogue" between pathways is the molecular basis of their synergy.

IL-18 activity is tightly regulated by its natural antagonist—IL-18 binding protein (IL-18BP). Disruption of the IL-18/IL-18BP balance is central to many diseases.

Macrophage activation syndrome and adult-onset Still's disease: In these diseases, patients exhibit extremely elevated serum IL-18 levels (up to thousands of times normal levels), with insufficient compensatory increases in IL-18BP, leading to abnormally high levels of free IL-18. Excessive IL-18 drives hyperactivation of NK and T cells, resulting in a "cytokine storm" that causes life-threatening symptoms such as persistent fever, hepatosplenomegaly, and pancytopenia. Anti-IL-18 monoclonal antibodies (e.g., Tadekinig alfa) show great potential in treating such diseases.

Systemic lupus erythematosus: Elevated serum IL-18 levels correlate with disease activity, likely contributing to pathogenesis by promoting IFN-γ production and Th1 responses.

Inflammatory bowel disease: In Crohn's disease patients, elevated IL-18 levels in the intestinal mucosa may exacerbate intestinal inflammation and damage through multiple mechanisms.

Protective role: In defending against viral (e.g., influenza virus, herpes simplex virus) and intracellular bacterial (e.g., Mycobacterium tuberculosis, Listeria) infections, IL-12/IL-18 synergy-induced IFN-γ is a key protective mechanism.

Pathogenic role: In certain chronic viral infections (e.g., HIV) or severe bacterial infections (e.g., sepsis), uncontrolled excessive IL-18 release may lead to harmful systemic inflammation and multi-organ damage.

Obesity and type 2 diabetes: In adipose tissue of obese individuals, NLRP3 inflammasome activation leads to increased IL-18 production. Moderate IL-18 levels positively maintain metabolic homeostasis, but chronic high levels may promote low-grade inflammation, contributing to insulin resistance.

Complex dual role: On one hand, IL-18 can exert anti-tumor effects by activating NK cells and CTLs and has been tested in cancer clinical trials as a recombinant cytokine (though limited efficacy and toxicity hindered progress). On the other hand, in the tumor microenvironment, IL-18 may be exploited by tumor cells or immunosuppressive cells to induce PD-1 expression or enhance regulatory T cell function, thereby exerting immunosuppressive effects. This paradoxical role complicates its application in cancer therapy.

Deeper understanding of IL-18's pathological roles is driving new therapeutic strategies, with the core focus on restoring its physiological balance.

Neutralizing antibodies: Monoclonal antibodies targeting IL-18 or IL-18R provide precise tools for treating IL-18-driven hyperinflammatory diseases (e.g., MAS, AOSD).

Recombinant IL-18BP: As a natural, high-affinity IL-18 inhibitor, recombinant IL-18BP is another promising therapeutic approach to neutralize excessive free IL-18.

Serum IL-18 levels, especially the "free IL-18" index calculated as the ratio to IL-18BP, have become a sensitive and specific biomarker for diagnosing and monitoring diseases like macrophage activation syndrome.

Local delivery strategies: To avoid systemic toxicity, new research focuses on engineered cell carriers (e.g., CAR-T cells) or oncolytic viruses to locally express IL-18 in the tumor microenvironment, aiming to safely activate immune responses.

Overcoming immunosuppressive functions: In-depth study of IL-18's pro-immunosuppressive mechanisms in specific tumor microenvironments and development of combination strategies (e.g., with PD-1 inhibitors) to counteract this paradox.

Since IL-18 maturation depends on the NLRP3 inflammasome, developing NLRP3 inhibitors may reduce IL-1β and IL-18 release, offering potential treatments for various diseases associated with excessive inflammasome activation.

Interleukin-18 is a sophisticated "alarm amplifier" system of the immune system. Stored as an inert precursor, it ensures release only upon genuine danger (inflammasome activation). Its effects are not autonomous but highly dependent on synergistic signals (e.g., IL-12), enabling it to serve as both a potent weapon against infections and tumors and, when dysregulated, a trigger for lethal "cytokine storms." From its role as a core mediator and biomarker in autoinflammatory diseases to the renewed scrutiny of its complex role in cancer immunotherapy, IL-18 research highlights the delicate balance of immune regulation. Moving forward, by precisely identifying contexts where it exerts beneficial or harmful effects and employing interventions such as neutralizing antibodies, natural antagonists, or localized delivery strategies, we can more safely and effectively harness this powerful inflammatory force, opening new avenues for treating various immune dysregulation-related diseases.