HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/F1234    most recent 00388.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Giannopoulou, M. Articles by Liu, Y. Search for Related Content PubMed PubMed Citation Articles by Giannopoulou, M. Articles by Liu, Y.

Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon- inhibition of TGF-₁ action

¹Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ²Department of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

Submitted 27 September 2005 ; accepted in final form 29 November 2005

Interferon- (IFN-) is a multifunctional cytokine that elicits antifibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN- in modulating the fibrogenic action of transforming growth factor (TGF)-₁ in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN- inhibited TGF-₁-mediated -smooth muscle actin (-SMA) expression. IFN- also abolished TGF-₁-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF- inhibits TGF-₁ action, the signaling pathways that are critical for mediating the antifibrotic activity of IFN- were studied. Stimulation of HKC cells with IFN- triggered a sustained activation of Erk-1/2 and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with an Mek1 inhibitor abolished the inhibitory effect of IFN- on -SMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN- and suppressed TGF-₁-mediated -SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN- to attenuate TGF-₁-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN- is capable of antagonizing the fibrogenic actions of TGF-₁ in renal tubular epithelial cells. The antifibrotic action of IFN- appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.

transforming growth factor-; signal transducer and activator of transcription-3; renal fibrosis

This article has been cited by other articles:

				J. E. Harris, M. Fernandez-Vilaseca, P. T. G. Elkington, D. E. Horncastle, M. B. Graeber, and J. S. Friedland IFN{gamma} synergizes with IL-1{beta} to up-regulate MMP-9 secretion in a cellular model of central nervous system tuberculosis FASEB J, February 1, 2007; 21(2): 356 - 365. [Abstract] [Full Text] [PDF]

				Y. Yang, X. Pan, W. Lei, J. Wang, J. Shi, F. Li, and J. Song Regulation of Transforming Growth Factor-{beta}1-Induced Apoptosis and Epithelial-to-Mesenchymal Transition by Protein Kinase A and Signal Transducers and Activators of Transcription 3. Cancer Res., September 1, 2006; 66(17): 8617 - 8624. [Abstract] [Full Text] [PDF]