title: Attenuation of transforming growth factor-β-stimulated collagen production in fibroblasts by quercetin-induced heme oxygenase-1.
abstract: Quercetin is a flavonoid with a wide variety of cytoprotective and modulatory functions. Heme oxygenase-1 (HO-1) is an inducible enzyme. Its reaction product, carbon monoxide (CO), confers cellular protection in a number of conditions and diseases associated with oxidative or inflammatory lung injury. Furthermore, quercetin was reported to be a potent inducer of HO-1 in several cell types. We hypothesized that quercetin suppresses the production of collagen in fibroblasts via the induction of HO-1. Here, we showed that quercetin suppresses transforming growth factor-β (TGF-β)-induced collagen production in NIH3T3 cells and in normal human lung fibroblasts. This suppressive effect of quercetin was mediated by quercetin-induced HO-1. The suppression of collagen production was conferred by the reaction product of HO-1, CO, but not by bilirubin. Furthermore, the translocation of the nuclear factor E2-related factor-2 (Nrf2), an important transcription factor that regulates the expression of HO-1 from the cytoplasm to the nuclei, was demonstrated in NIH3T3 cells by exposure to quercetin. Assessment of the signal transduction pathway involved in TGF-β signaling showed that quercetin stimulated the Smad and mitogen-activated protein kinase pathway to varying degrees. Our results demonstrate that quercetin exerts suppressive effects on the expression of collagen by the induction of HO-1. Idiopathic pulmonary fibrosis is the most lethal diffuse fibrosing lung disease, and is characterized by the deposition of extracellular matrix. Given that HO-1 is one of the important molecules emerging as a central player in diseases, quercetin or its derivatives, which effectively induced HO-1, will lead to new therapeutic strategies for promoting antifibrotic therapy in respiratory diseases.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Nagoya University, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Miyoko
authors.initials: M
authors.lastname: Matsushima
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Masataka
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimokata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawabe
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D041681:NIH 3T3 Cells; D011658:Pulmonary Fibrosis / Q000473:pathology; D011794:Quercetin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D003094:Collagen; D011794:Quercetin; D051547:Heme Oxygenase-1