Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis

• Published in: The Journal of experimental medicine Vol. 206; no. 5; pp. 1149 - 1166
• Main Authors: Lee, Chun Geun, Hartl, Dominik, Lee, Gap Ryol, Koller, Barbara, Matsuura, Hiroshi, Da Silva, Carla A, Sohn, Myung Hyun, Cohn, Lauren, Homer, Robert J, Kozhich, Alexander A, Humbles, Alison, Kearley, Jennifer, Coyle, Anthony, Chupp, Geoffrey, Reed, Jennifer, Flavell, Richard A, Elias, Jack A
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 11-05-2009
• Subjects: Adipokines; Animals; Apoptosis - genetics; Apoptosis - physiology; Asthma - genetics; Chitinase-3-Like Protein 1; Conserved Sequence; Coronary Disease - genetics; Glycoproteins - deficiency; Glycoproteins - genetics; Glycoproteins - therapeutic use; Humans; Immunoglobulin E - immunology; Inflammation - chemically induced; Inflammation - genetics; Inflammation - pathology; Interleukin-13 - genetics; Lectins; Mice; Mice, Knockout; Mice, Transgenic; Ovalbumin
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20081271

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.