Full-length IL-33 promotes inflammation but not Th2 response in vivo in an ST2-independent fashion

• Published in: The Journal of immunology (1950) Vol. 189; no. 1; pp. 403 - 410
• Main Authors: Luzina, Irina G, Pickering, Edward M, Kopach, Pavel, Kang, Phillip H, Lockatell, Virginia, Todd, Nevins W, Papadimitriou, John C, McKenzie, Andrew N J, Atamas, Sergei P
• Format: Journal Article
• Language: English
• Published: United States 01.07.2012
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Female; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; HEK293 Cells; Humans; Inflammation Mediators - administration & dosage; Inflammation Mediators - adverse effects; Inflammation Mediators - physiology; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins - adverse effects; Interleukins - biosynthesis; Interleukins - physiology; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis - immunology; Pulmonary Fibrosis - immunology; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Receptors, Interleukin - deficiency; Receptors, Interleukin - genetics; Receptors, Interleukin - physiology; Stem Cells - immunology; Stem Cells - metabolism; Stem Cells - pathology; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - pathology
• DOI: 10.4049/jimmunol.1200259
• ISSN: 0022-1767

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 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 mm IL-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 mm IL-33-induced Th2-associated effects (pulmonary eosinophilia, goblet cell hyperplasia, and increased IL-4 and IL-5), yet the lymphocytic infiltration induced by full-length mouse IL-33 or mm IL-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 3, 10, and 13. 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-33R chain ST2, whereas their similar effects result from regulation of gene expression.