Clara cell 10-kD protein suppresses chitinase 3-like 1 expression associated with eosinophilic chronic rhinosinusitis.
BACKGROUND
Clara cell 10-kD (CC10) protein, an antiinflammatory molecule, is involved in inflammatory upper airway diseases, but its regulatory role is unclear, particularly in the process of chronic rhinosinusitis (CRS).


OBJECTIVE
To investigate the regulatory mechanisms of CC10 in eosinophilic CRS (ECRS) using an allergic mouse model.


METHODS
Homozygous CC10-knockout mice were used to establish an allergic ECRS model. Phenotypic changes were examined by histology, cytokine ELISA, and gene microarray analysis. Differential expression of chitinase 3-like 1 (CHI3L1) was verified by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. The functional role of CHI3L1 in vivo was assessed by the use of anti-CHI3L1 antibody in ECRS mice. CHI3L1 gene expression regulated by inflammatory cytokines and CC10 protein was performed using BEAS-2B cell line.


RESULTS
Compared with wild-type mice, a significantly greater extent of inflammatory cell infiltration and tissue remodeling was found in CC10-knockout ECRS mice, which was associated with significantly higher levels of various cytokines and eotaxin-1. CHI3L1 was up-regulated in ECRS mice with a significant further increase in CC10-knockout mice. Anti-CHI3L1 treatment markedly ameliorated eosinophilic inflammation. Furthermore, nasal mucosal CC10 gene transfer in CC10-knockout mice attenuated eosinophilic inflammation and suppressed the levels of CHI3L1. Moreover, significantly up-regulated expression of CHI3L1 was noted in human ECRS. IL-1beta, tumor necrosis factor-alpha, and IL-13 were found to up-regulate CHI3L1 expression in BEAS-2B cells, whereas CC10 inhibited such up-regulation.


CONCLUSIONS
These results suggest that CHI3L1 is a novel molecule involved in ECRS and that CC10 plays a regulatory role in ECRS, presumably by attenuating CHI3L1 expression.
Wang
Heng
H
Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.
Long
Xiao-Bo
XB
Cao
Ping-Ping
PP
Wang
Nan
N
Liu
Yang
Y
Cui
Yong-Hua
YH
Huang
Shau-Ku
SK
Liu
Zheng
Z
D054392:Adipokines; D056151:Airway Remodeling / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000032:analysis; D000071451:Chitinase-3-Like Protein 1; D002908:Chronic Disease; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D004802:Eosinophilia / Q000503:physiopathology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D037102:Lectins / Q000032:analysis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012220:Rhinitis / Q000503:physiopathology*; D012852:Sinusitis / Q000503:physiopathology*; D015854:Up-Regulation; D014598:Uteroglobin / Q000235:genetics / Q000502:physiology*
D054392:Adipokines; C084533:CHI3L1 protein, human; D054413:Chemokine CCL11; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines; D006023:Glycoproteins; D037102:Lectins; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D014598:Uteroglobin