FULL-LENGTH INTERLEUKIN-33 PROMOTES INFLAMMATION BUT NOT TH2 RESPONSE IN VIVO IN AN ST2-INDEPENDENT FASHION

Expression of IL-33 is elevated in patients with pulmonary diseases, and full-length (not proteolytically processed) IL-33 is the predominant form in the lungs in health and disease. To determine whether activation of IL-33 is needed for functional effects, activities of full-length mouse (flm) and mature mouse (mm) forms of IL-33 were compared in vivo . Replication-deficient adenoviral constructs were used for gene delivery. Both isoforms caused pulmonary infiltration of lymphocytes and neutrophils, whereas mmIL-33 also caused pulmonary eosinophilia and goblet cell hyperplasia, and increased expression of IL-4, IL-5, IL-13, IL-17, MCP-1, and KC. The different effects were not associated with differential release from IL-33-producing cells or by differences in subcellular distributions of IL-33 isoforms. Germline deficiency of the cell surface receptor chain ST2 abrogated the mmIL-33-induced Th2-associated effects (pulmonary eosinophilia, goblet cell hyperplasia, and increased IL-4 and IL-5), yet the lymphocytic infiltration induced by flmIL-33 or mmIL-33 was not fully abrogated by the absence of ST2. The similar effects of IL-33 isoforms were associated with comparable regulation of gene expression, notably matrix metalloproteinases MMP3, MMP10, and MMP13. Thus, full-length IL-33 is functionally active in vivo in an ST2-independent fashion, and its effects are partially different from those of mature IL-33. The different effects of these isoforms, particularly the pro-Th2 effects of mature IL-33, are due to differential utilization of the IL-33 receptor chain ST2, whereas their similar effects result from regulation of gene expression.