TY - JOUR T1 - Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3 JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900350 VL - 2 IS - 3 SP - e201900350 AU - Chang-Min Lee AU - Chuan-Hua He AU - Jin Wook Park AU - Jae Hyun Lee AU - Suchitra Kamle AU - Bing Ma AU - Bedia Akosman AU - Roberto Cotez AU - Emily Chen AU - Yang Zhou AU - Erica L Herzog AU - Changwan Ryu AU - Xueyan Peng AU - Ivan O Rosas AU - Sergio Poli AU - Carol Feghali Bostwick AU - Augustine M Choi AU - Jack A Elias AU - Chun Geun Lee Y1 - 2019/06/01 UR - https://www.life-science-alliance.org/content/2/3/e201900350.abstract N2 - TGF-β1 is a critical mediator of tissue fibrosis in health and disease whose effects are augmented by chitinase 1 (CHIT1). However, the mechanisms that CHIT1 uses to regulate TGF-β1–mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-β1–stimulated fibrotic cellular and tissue responses and TGF-β1 signaling. Importantly, we also demonstrate that these effects are mediated by the ability of CHIT1 to inhibit TGF-β1 induction of its feedback inhibitor, SMAD7. CHIT1 also interacted with TGF-β receptor associated protein 1 (TGFBRAP1) and forkhead box O3 (FOXO3) with TGFBRAP1 playing a critical role in CHIT1 enhancement of TGF-β1 signaling and effector responses and FOXO3 playing a critical role in TGF-β1 induction of SMAD7. These pathways were disease relevant because the levels of CHIT1 were increased and inversely correlated with SMAD7 in tissues from patients with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease. These studies demonstrate that CHIT1 regulates TGF-β1/SMAD7 axis via TGFBRAP1 and FOXO3 and highlight the importance of these pathways in the pathogenesis of pulmonary fibrosis. ER -