IL-33 precursor (IL33PR) released from damaged cells is known to bind to the receptor T1/ST2 and activate cells in culture. However, we found that in patients with interstitial lung diseases (ILD) and in the bleomycin mouse model of lung injury, pulmonary expression of IL33PR is elevated intracellularly and intranuclearly. Recombinant adenoviral gene delivery of IL33PR to mouse lungs in vivo did not lead to IL-33 maturation and produced a phenotype that was strikingly different from that induced by mature IL33 (MIL33). IL33PR induced pulmonary lymphocytosis and neutrophilia, whereas MIL33 induced eosinophilia, goblet cell hyperplasia, and increases in Th2 cytokines. The effects of MIL33 were, but the effects of IL33PR were not, abrogated by gene deficiency of T1/ST2. When combined with bleomycin injury, IL33PR potentiated lymphocytosis, collagen accumulation, and the expression of proinflammatory and profibrotic cytokines TGF-β, IL-6, MCP-1, and MIP-1α in the lungs. Gene expression profiling in cultured fibroblasts and epithelial cells overexpressing IL33PR revealed 10 - 100 fold increases in HSP70 mRNA, further confirmed by RT-Q-PCR. Previous reports have associated HSP70 with ILD. Immunohistochemical analyses showed strong HSP70 protein increases in mice challenged with bleomycin, IL33PR gene delivery, and particularly in mice challenged with these factors combined. Thus, IL33PR promotes ILD by inducing proinflammatory and profibrotic cytokines and HSP70.
- Copyright © 2013 by The American Association of Immunologists, Inc.