Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis.
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.
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Chun Geun
CG
Lee
Dominik
D
Hartl
Gap Ryol
GR
Lee
Barbara
B
Koller
Hiroshi
H
Matsuura
Carla A
CA
Da Silva
Myung Hyun
MH
Sohn
Lauren
L
Cohn
Robert J
RJ
Homer
Alexander A
AA
Kozhich
Alison
A
Humbles
Jennifer
J
Kearley
Anthony
A
Coyle
Geoffrey
G
Chupp
Jennifer
J
Reed
Richard A
RA
Flavell
Jack A
JA
Elias
D054392:Adipokines; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001249:Asthma / Q000235:genetics; D000071451:Chitinase-3-Like Protein 1; D017124:Conserved Sequence; D003327:Coronary Disease / Q000235:genetics; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D018793:Interleukin-13 / Q000235:genetics*; D037102:Lectins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin
D054392:Adipokines; C084533:CHI3L1 protein, human; C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D018793:Interleukin-13; D037102:Lectins; D007073:Immunoglobulin E; D010047:Ovalbumin