Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis
Open Access
- 4 May 2009
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 206 (5), 1149-1166
- https://doi.org/10.1084/jem.20081271
Abstract
Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39−/− mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium. Studies of these mice demonstrated that BRP-39−/− animals have markedly diminished antigen-induced Th2 responses and that epithelial YKL-40 rescues the Th2 responses in these animals. The ability of interleukin13 to induce tissue inflammation and fibrosis was also markedly diminished in the absence of BRP-39. Mechanistic investigations demonstrated that BRP-39 and YKL-40 play an essential role in antigen sensitization and immunoglobulin E induction, stimulate dendritic cell accumulation and activation, and induce alternative macrophage activation. These proteins also inhibit inflammatory cell apoptosis/cell death while inhibiting Fas expression, activating protein kinase B/AKT, and inducing Faim 3. These studies establish novel regulatory roles for BRP-39/YKL-40 in the initiation and effector phases of Th2 inflammation and remodeling and suggest that these proteins are therapeutic targets in Th2- and macrophage-mediated disorders.Keywords
This publication has 54 references indexed in Scilit:
- Acidic Mammalian Chitinase Is Secreted via an ADAM17/Epidermal Growth Factor Receptor-dependent Pathway and Stimulates Chemokine Production by Pulmonary Epithelial CellsOnline Journal of Public Health Informatics, 2008
- Effect of Variation inCHI3L1on Serum YKL-40 Level, Risk of Asthma, and Lung FunctionThe New England Journal of Medicine, 2008
- High serum YKL-40 level in a cohort of octogenarians is associated with increased risk of all-cause mortalityClinical and Experimental Immunology, 2007
- SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signalingJCI Insight, 2007
- Life and death in peripheral T cellsNature Reviews Immunology, 2007
- Bid activation during induction of extrinsic and intrinsic apoptosis in eosinophilsImmunology & Cell Biology, 2007
- Semaphorin 7A plays a critical role in TGF-β1–induced pulmonary fibrosisThe Journal of Experimental Medicine, 2007
- Chitin induces accumulation in tissue of innate immune cells associated with allergyNature, 2007
- Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosisJCI Insight, 2006
- Trauma increases extrahepatic arginase activitySurgery, 2000