Full-length IL-33 acts differently from mature IL-33 in vivo partially in an ST2-independent fashion (120.30)

Abstract IL-33 is a key regulator of inflammation and immunity. It remains controversial whether protease-mediated activation of IL-33 is needed for functional effects. We constructed and validated recombinant adenoviruses for gene delivery of full-length mouse (flm) and mature mouse (mm) (aa 109-266) IL-33 to mouse lungs in vivo. Gene expression was confirmed by RT-Q-PCR and ELISA. Analyses of BAL samples and lung tissues revealed substantial differences between flmIL-33 and mmIL-33. Both isoforms caused pulmonary infiltration and BAL influx of T and B lymphocytes and neutrophils, whereas mmIL-33 also caused significant pulmonary eosinophilia (~47-55% of BAL cell count) and hyperplasia of mucus-producing goblet cells. Multiplex analyses showed that mmIL-33 caused significant increases in IL-4, IL-5, IL-13, IL-17, and KC; flmIL-33 tended to stimulate IFN-γ; and both isoforms induced MCP-1 with a greater increase induced by mmIL-33. Subsequent analyses were performed in mice deficient of ST2 (IL-33 receptor). ST2 deficiency completely abrogated mmIL-33-induced pulmonary eosinophilia, goblet cell hyperplasia, and elevations in IL-4 and IL-5. However, lymphocytic infiltration induced by flmIL-33 or mmIL-33 was attenuated but persistent in the absence of ST2. These data suggest that full-length IL-33 is independently functionally active in vivo, in part in an ST2-independent fashion, and that Th2 effects but not lymphocytosis induced by mature IL-33 are ST2-dependent.