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Published ahead of print on January 14, 2005, doi:10.1165/rcmb.2004-0288OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 4, April 2005, 342-349

A more recent version of this article appeared on April 1, 2005
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Submitted on September 13, 2004
Revised on January 13, 2005

TNF-{alpha} Induces TGF-{beta}1 Expression in Lung Fibroblasts Through the ERK Pathway

Deborah E Sullivan1*, MaryBeth Ferris1, Derek Pociask1, and Arnold R Brody1

1 Department of Pathology and Laboratory Medicine and the Lung Biology Program, Tulane University Health Sciences Center, New Orleans, LA, USA

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

Increased expression of transforming growth factor (TGF)-{beta}1 and tumor necrosis factor (TNF)-{alpha} are thought to play important roles in the development of pulmonary fibrosis. We recently reported that TNF-{alpha} upregulates TGF-{beta}1 expression in primary mouse lung fibroblasts (MLFs), a key cell population in fibrogenesis. In the present study, we have investigated signal transduction pathways involved in TNF-{alpha} upregulation of TGF-{beta}1 in both primary MLFs and the Swiss 3T3 fibroblast cell line. Treatment of fibroblasts with TNF-{alpha} resulted in a significant increase in TGF-{beta}1 protein as measured by ELISA. The increase in protein was preceded by a 200-400% increase in TGF-{beta}1 mRNA detected by quantitative, real-time, reverse transcriptase-polymerase chain reaction. Western blot analysis showed that TNF-{alpha} activated the extracellular signal-regulated kinase (ERK) and inhibitors of the ERK-specific mitogen activated protein kinase (MAPK) pathway (PD98059 or U0126) blocked TNF-{alpha} induction of TGF-{beta}1 mRNA and protein. mRNA stability experiments showed that TNF-{alpha} increased the half-life of TGF-{beta}1 mRNA to more than 24 h compared to ~ 15 h in unstimulated cells. Expression of constitutively active MEK1 that selectively phosphorylates ERK was sufficient for TGF-{beta}1 mRNA stabilization in Swiss 3T3 fibroblasts. These results indicate that TNF-{alpha} activates the ERK-specific MAPK pathway leading to increased TGF-{beta}1 production in fibroblasts, primarily via a posttranscriptional mechanism that involves stabilization of the TGF-{beta}1 transcript.




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Copyright © 2005 American Thoracic Society. 		  2009 ATS Conference