Attenuation of transforming growth factor-β-stimulated collagen production in fibroblasts by quercetin-induced heme oxygenase-1

Am J Respir Cell Mol Biol. 2011 May;44(5):614-20. doi: 10.1165/rcmb.2010-0338OC. Epub 2011 Jan 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Cell Nucleus / metabolism
  • Collagen / chemistry
  • Collagen / metabolism*
  • Cytoplasm / metabolism
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Immunohistochemistry / methods
  • Mice
  • NIH 3T3 Cells
  • Pulmonary Fibrosis / pathology
  • Quercetin / pharmacology*
  • Transforming Growth Factor beta / metabolism*


  • Antioxidants
  • Enzyme Inhibitors
  • Transforming Growth Factor beta
  • Collagen
  • Quercetin
  • Heme Oxygenase-1