Production and functions of IL-33 in the central nervous system

Interleukin-33 (IL-33) is a novel multifunctional IL-1 family cytokine. IL-33 signals via a heterodimer composed of IL-1 receptor-related protein ST2 and IL-1 receptor accessory protein (IL-1RAcP). IL-33 has been shown to activate T helper 2 cells (Th2), mast cells and basophils to produce a variety of Th2 cytokines and mediate allergic-type immune responses. Recent studies have revealed that glial cells are induced to express IL-33 mRNA and protein. However, the functions of IL-33 and its producing cells in the central nervous system (CNS) are still uncertain. In this study, we investigated the expression and function of IL-33 in the CNS. IL-33 is produced by endothelial cells and astrocytes but not by microglia or neurons. The IL-33 receptors are expressed mainly in microglia and astrocytes. IL-33 dose-dependently induces the proliferation of microglia and enhances the production of pro-inflammatory cytokines, such as IL-1β and TNFα, as well as the anti-inflammatory cytokine IL-10. It also enhances chemokines and nitric oxide production and phagocytosis by microglia. Thus, IL-33 produced in the CNS activates microglia and may function as a pro-inflammatory mediator in the pathophysiology of the CNS.