The IL-1 family of cytokines comprises 11 members, including 7 agonists (IL-1a, IL-1b, IL-18, IL-33, IL-36a, IL-36b, IL-36g), 2 established antagonists (IL-1Ra, IL-36Ra) and 2 additional cytokines (IL-37, IL-38) the biological functions of which are not fully established. I will show some of our findings on IL-36 and IL-18.
We have shown that IL-36 agonists stimulate dendritic cells and naïve T cells to produce Th1 responses. To examine the role of IL-36 as a vaccine adjuvant to vaccines to induce Th1 responses, new-born mice were injected with tetanus toxoid-Alum with or without IL-36. We observed that the addition of IL-36 is associated with a high lethality due to a cytokine storm mediated by TNF-a. We have also examined the role of IL-36R signaling in a Th1 model of host defense. IL-36R-/-, IL-1R-/- and TNF-a-/- and wild-type (WT) mice were infected with M. tuberculosis. We observed that, in contrast to TNF-a and IL-1R, IL-36R signaling is dispensable to control of M. tuberculosis infection.
The biological effects of IL-18 are tightly regulated at the level of its production and maturation as well as by a soluble inhibitor, IL-18 binding protein (IL-18BP). We developed an assay to specifically measure free IL-18 in human and mouse and found that levels of free IL-18 are elevated in some autoinflammatory diseases, including adult onset Still’s disease (AOSD). We conducted a phase 2 clinical trial with recombinant IL-18BP in patients with AOSD and obtained positive results with 50% response in patients with refractory disease. By using IL-18BP-/- mice in a model of macrophage activation syndrome induced by repeated CpG injections, we showed that unopposed IL-18 signaling leads to severe manifestations.
In conclusion, IL-36 is dispensable in host defense against M. tuberculosis. IL-18 is an interesting target for future therapy in some autoinflammatory diseases.