Interleukin-18: Biological properties and role in disease pathogenesis

Abstract

Initially described as an interferon (IFN)γ-inducing factor, interleukin (IL)-18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17-producing γδ T cells and macrophage activation. IL-18, a member of the IL-1 family, is similar to IL-1β for being processed by caspase 1 to an 18 kDa-biologically active mature form. IL-18 binds to its specific receptor (IL-18Rα, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rβ chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Rα may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP.

Keywords: hemophagocytic syndromes; inflammatory diseases; interferon γ; interleukin-1; interleukin-18; interleukin-18 binding protein.

Figure 1

IL‐18 regulation by IL‐18 binding protein and IL‐37. IL‐18 binds the ligand receptor IL‐18Rα, inducing the recruitment of IL‐18Rβ to form a high affinity receptor. The Toll‐IL‐1R Receptor (TIR) domains approximate and allow the binding of MyD88, then inducing a pro‐inflammatory signal into the cells terminating in NF‐κB activation. IL‐18 binding protein (IL‐18BP) which is present in the extracellular compartment may bind soluble mature IL‐18 with a higher affinity than IL‐18Rα and prevents IL‐18 binding to IL‐18 receptor. IL‐18BP may also bind IL‐37, preventing its binding to IL‐18Rα. Free IL‐37 binds to IL‐18Rα inducing the recruitment of IL‐1R8 to form a high affinity receptor, which does not bind MyD88, but induces instead an anti‐inflammatory signal into the cell

Figure 2

Biological functions of IL‐18. Activation of dendritic cells (DC) or macrophages may induce IL‐18 precursor transcription, but IL‐18 precursor is also constitutively present in the cells. Upon activation of NLRP3, pro‐IL‐18 is processed by caspase 1 and released in its 18 kDa‐mature form. In association with IL‐12 or IL‐15 which increase IL‐18Rβ expression on T cells, IL‐18 induces IFNγ production by CD4 T cells. IFNγ in turn, activates macrophages to produce inflammatory cytokines. IL‐18 can also activate macrophages directly to induce chemokine secretion and NK cells to induce IFNγ secretion or to stimulate perforin‐ and FasL‐mediated cytotoxicity. In macrophages, the interaction of FasL with Fas induces IL‐18 processing by caspase 8. Alternatively, in the absence of IL‐12 or IL‐15, IL‐18 activates Th2 CD4 lymphocytes to produce IL‐13 and IL‐4

Figure 3

Role of IL‐18 in inflammatory bowel diseases. In homeostatic conditions (A), IL‐18 is produced by intestinal epithelial cells (IEC) after processing by NLRP3 or NLRP6 inflammasomes. IL‐18 has a protective role on intestinal barrier through mucus synthesis by goblet cells (green triangles) or secretion of anti‐microbial peptides (AMP) by IEC. In this way, IL‐18 maintains a normal microbiota in the digestive tract. In case commensal bacteria enter the mucosa (pink arrow), macrophages from the lamina propria secrete IL‐18 which controls infection and IL‐1β which has healing properties. In pathogenic conditions (B), the epithelial barrier is disrupted and bacteria enter massively in the lamina propria where they induce local macrophages to produce IL‐18 which is detrimental (purple) and IL‐1β (pink) which is protective. Disrupted IEC also release IL‐1α which is highly proinflammatory in this setting (purple) and activates macrophages. This leads to chemokine secretion and leukocyte recruitment from the peripheral blood into the lamina propria. In the meantime, IL‐18 inhibits mucus production by goblet cells and modify microbiota favoring dysbiosis