99 : IL-33 splice variants are critical to its regulated secretion from airway epithelial cells

Abstract

IL-33 is a member of the IL-1 family of cytokines. It plays a critical role in allergic disease as an upstream regulator of Th2 type inflammation, and multiple genome wide association studies have implicated this cytokine in the pathogenesis of asthma. IL-33 localizes in the airway to the nuclei of airway epithelial basal cells. To date, the mechanisms of its release from epithelial cells have been elusive. Furthermore, its precise role and regulation in the asthmatic airway remains unclear. Recently, we discovered that IL-33 splice variants transcripts are present in human airway epithelial cells. Furthermore, we find that splice variants vary in their localization to the nucleus or cytoplasm. We have gone onto show that following stimulation of airway epithelial cells with secretogogues, cytoplasmic IL-33 variants are released extracellularly while nuclear forms are not. Finally, we find by immunoblot that IL-33 present in the airway secretions of asthmatics is a truncated form of the protein (not full length) and contains both the N and C terminus, arguing against proteolytic degradation of the IL-33 protein in vivo. These studies provide new insights to the mechanisms that airway epithelial cells use to regulate the secretion of this important Th2 cytokine and help to inform the development of anti-IL-33 therapeutics.