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¹ Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, ² Section of Immunobiology, and ³ Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
⁴ MedImmune, Inc., Gaithersburg, MD 20878

CORRESPONDENCE Jack A. Elias: Jack.elias{at}yale.edu

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.

G.R. Lee’s present address is Dept. of Life Science, Sogang University, Seoul, Korea.

Abbreviations used: AHR, airways hyperresponsiveness; alum, aluminum hydroxide; AMCase, acidic mammalian chitinase; BAL, bronchoalveolar lavage; BRP-39, breast regression protein 39; CLP, chitinase-like protein; dox, doxycycline; Faim, Fas apoptosis-inhibiting molecule; HcGP, human cartilage glycoprotein; HDM, house dust mite; IHC, immunohistochemistry; mDC, myeloid DC; MMR, macrophage mannose receptor; mRNA, messenger RNA; pDC, plasmacytoid DC; PI, propidium iodide; PKB, protein kinase B; TARC, thymus- and activation-regulated chemokine; Tg, transgenic.

© 2009 Lee et al.
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