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Published ahead of print on January 12, 2004, doi:10.1165/rcmb.2002-0249OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 6, June 2004, 816-822

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Submitted on November 13, 2002
Revised on January 7, 2004

IFN-{gamma} inhibits TGF-{beta} production in human airway epithelial cells by targeting Smads

Fu-Qiang Wen1, Xiangde Liu1, Tetsu Kobayashi1, Shinji Abe1, Qiuhong Fang1, Tadashi Kohyama2, Ronald Ertl1, Yusuke Terasaki1, Lidia Manouilova1, and Stephen I Rennard1*

1 Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA, 2 Respiratory Medicine, University of Tokyo, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.

Since IFN-{gamma} may attenuate pulmonary fibrosis, we hypothesized that IFN-{gamma} may regulate TGF-{beta} production by airway epithelial cells. Human bronchial epithelial cells (HBECs) were incubated with IFN-{gamma} ± TGF-{beta}1, {beta}3 or IL-1{beta}, PDGF, EGF and IL-4. TGF-{beta}2 protein was measured by ELISA and mRNA expression for TGF-{beta}2, Smad 2, 3, 4 and 7 was evaluated by real time RT-PCR. Localization of Smads 2, 3, 4, and 7 was evaluated by immunostaining. Exogenous TGF-{beta}1 and 3, IL-1{beta}, PDGF and IL-4 enhanced TGF-{beta}2 release by HBECs (p<0.01). IFN-{gamma} reduced basal and TGF-{beta} or IL-4-augmented TGF-{beta}2 release, but had little effect on IL-1{beta}-, or PDGF-augmented TGF-{beta}2 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-{beta}2 production was abrogated when the HBECs were treated with Smad 7 siRNA. These results suggest that IFN-{gamma} down-regulates TGF-{beta}2 production by HBECs by regulating Smad 7. Through this mechanism, IFN-{gamma} may play an important role in tissue remodeling.




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