Clara Cell 10-kD Protein Suppresses Chitinase 3-Like 1 Expression Associated with Eosinophilic Chronic Rhinosinusitis

Abstract

Rationale: 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). Objectives: 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. Measurements and Main 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-1b, tumor necrosis factor-a, 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.

Induced sputum proteome in healthy subjects and asthmatic patients

“…Allergen-challenged Scgb1a1 -null mice manifest an exaggerated allergic response withprofound pulmonary eosinophilia, elevation of Th2 cytokines, and development of eosinophilic chronic rhinosinusitis 32-34 . In humans, the number of SCGB1A1-positive airway epithelial cells are significantly reduced in asthmatics 35 and the serum levels of this protein are decreased 36 .…”

Clara Cell 10-kDa Protein Gene Transfection Inhibits NF-κB Activity in Airway Epithelial Cells

“…CC10 possesses anti-inflammatory and immunomodulatory effects. Compared with wild-type mice, CC10 knockout mice demonstrate exaggerated airway inflammation provoked by allergic responses and bacterial and viral infection [2]. Reduced levels of CC10 have been correlated with allergic and inflammatory airway diseases, including asthma, allergic rhinitis, and sinusitis [3], [4], [5].…”

Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation

“…CC10 mRNA expression in sinonasal mucosa is lower in subjects with allergic rhinitis, asthma, and chronic rhinosinusitis with nasal polyps [8,15,16], suggesting that CC10 may modulate allergic airway inflammation. CC10 also inhibits IL-13-induced chitinase 3-like 1 (CHI3L1) gene expression in BEAS-2B cells [25]. An intravenous injection of CC10 inhibited LPS-stimulated IL-6, IL-1b and tumour necrosis factor-a in perfusates from isolated rat lungs [26].…”