IL-33 (or IL-1F11) was recently identified as a ligand for the previously orphaned IL-1 family receptor T1/ST2. IL-33 belongs to the IL-1 family of cytokines and upon binding to T1/ST2 induces intracellular signals similar to those of IL-1. Previous studies have established that IL-33 and T1/ST2 exert key functions in Th2 responses. Mast cells are known to express T1/ST2. Besides their well-known function in allergy and host defense, mast cells have recently been shown to play an important role in experimental models of arthritis.
To examine the effect of IL-33 on P815 murine mastocytoma cells and primary mouse bone marrow-derived mast cells (BMMC).
IL-33 dose-dependently and time-dependently stimulated IL-6 secretion by P815 mastocytoma cells and BMMC. Both cell types express T1/ST2 as assessed by RT-PCR and FACS analysis. This effect was dependent on T1/ST2 binding. The addition of ST2-Fc on BMMC inhibited the stimulatory effect of IL-33, whereas etanercept had no effect. IL-1RAcP-Fc alone or in combination with ST2-Fc inhibited the effect of IL-33, indicating that IL-33 binds to these soluble receptors. In addition, IL-33 also induced IL-1β, TNFα, MCP-1, and PGD2 production in BMMC. By the RNase protection assay, we demonstrated that IL-33 increased IL-6 and IL-1β? mRNA expression. These effects of IL-33 appeared to occur independently of mast cell degranulation.
The results of this study show for the first time that IL-33, a novel member of the IL-1 family of cytokines, stimulates the production of proinflammatory mediators by mast cells in addition to its effect on Th2 responses. These findings open new perspectives for the treatment of inflammatory diseases by targeting IL-33.