title: Interferon-gamma inhibits transforming growth factor-beta production in human airway epithelial cells by targeting Smads.
abstract: Because interferon (IFN)-gamma may attenuate pulmonary fibrosis, we hypothesized that IFN-gamma may regulate transforming growth factor (TGF)-beta production by airway epithelial cells. Human bronchial epithelial cells (HBECs) were incubated with IFN-gamma +/- TGF-beta1, -beta3, or interleukin (IL)-1beta, platelet-derived growth factor (PDGF), epidermal growth factor, and IL-4. TGF-beta2 protein was measured by enzyme-linked immunosorbent assay and mRNA expression for TGF-beta2, Smad 2, 3, 4, and 7 was evaluated by real-time reverse transcriptase-polymerase chain reaction. Localization of Smads 2, 3, 4, and 7 was evaluated by immunostaining. Exogenous TGF-beta1 and 3, IL-1beta, PDGF, and IL-4 enhanced TGF-beta2 release by HBECs (P < 0.01). IFN-gamma reduced basal and TGF-beta or IL-4-augmented TGF-beta2 release, but had little effect on IL-1beta- or PDGF-augmented TGF-beta2 release. IFN-gamma stimulated Smad 7 protein and mRNA expression. Smad 7-specific siRNA decreased Smad 7 protein expression both in control and IFN-gamma-treated cells. The inhibitory effect of IFN-gamma on TGF-beta2 production was abrogated when the HBECs were treated with Smad 7 siRNA. These results suggest that IFN-gamma down regulates TGF-beta2 production by HBECs by regulating Smad 7. Through this mechanism, IFN-gamma may play an important role in tissue remodeling.
authors.affiliation: Department of Respiratory Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Wen
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Abe
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Fang
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kohyama
authors.forename: Ronald
authors.initials: R
authors.lastname: Ertl
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Lidia
authors.initials: L
authors.lastname: Manouilova
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D004815:Epidermal Growth Factor; D007371:Interferon-gamma