We were interested in interleukin (IL)-18 inducible genes, which may be a causative role of IL-18 related autoimmune diseases since blocking IL-18 reduces disease activity in rheumatoid arthritis and systemic inflammation in animals and in humans. We discovered a new cytokine IL-32 using IL-18 inducible DNA microarray. IL-32 has the ability to induce various cytokines, including human TNFα, IL-1β, and IL-6 as well as chemokines. IL-32 activates the typical cytokine signaling pathways of nuclear factor-kappa B and p38 mitogen-activated protein kinase. We first demonstrated biological functions and signal transduction for IL-32 as that of a typical cytokine. As with many cytokines, an abnormality of IL-32 regulation may contribute to health and disease. A single cytokine itself can have a profound impact in immune regulatory diseases as well as in cancer biology. For example, the blockade of TNFα activity is a highly effective therapeutic approach in rheumatoid arthritis, Crohn's Disease, and psoriasis. The induction of TNFα and other proinflammatory cytokines by IL-32 suggests that IL-32 plays an important role in autoimmune/inflammatory diseases.
We also investigated a new member of the IL-1 family ligand (IL-33/IL-1F11) that provokes Th2-type immune responses. IL-1 family ligand, including IL-33, does not possess a typical hydrophobic signal peptide and needs a processing enzyme for maturation. The recombinant pro-IL-33 was not cleaved by caspase-1, unlike IL-18 (IL-1F4). We suggest that the PR3 cleaved IL-33 and possess the dual function (activation/termination) in IL-33 biological activity. In addition, we identified and characterized a new IL-33 splice variant, which was a constitutively active IL-33 isoform. The existence of constitutively active spIL-33 suggests that the biological activity of IL-33 could be triggered by diverse stimulations during immune responses. The goal of research in cytokine laboratory is to understand the precise role of cytokine with basic research, which may contribute unresolved immune responses associated health and disease.