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J. Biol. Chem., Vol. 283, Issue 29, 20397-20407, July 18, 2008

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Transforming Growth Factor-β1 Induces Heparan Sulfate 6-O-Endosulfatase 1 Expression in Vitro and in Vivo^*

Xinping Yue¹, Xian Li, Hong T. Nguyen, Dawn R. Chin, Deborah E. Sullivan, and Joseph A. Lasky²

From the Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine and Department of Microbiology and Immunology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Transforming growth factor (TGF)-β1 plays an important role in the development of pulmonary fibrosis. In this study we examined the relationship between TGF-β1 stimulation and the expression of heparan sulfate (HS) 6-O-endosulfatase 1 (Sulf1) in cultured normal human lung fibroblasts (NHLFs) and in murine lungs in vivo. By removing 6-O-sulfates from specific HS intrachain sites on the cell surface, Sulf1 has been shown to modulate the activities of many HS binding growth factors and morphogens including fibroblast growth factor (FGF)-2. Real time reverse transcription-PCR analysis revealed that TGF-β1 increased Sulf1 expression in NHLFs in a dose- and time-dependent manner which was accompanied by a decrease in 6-O-sulfated disaccharides as revealed by high performance liquid chromatography analysis. Decreased ERK activation after FGF-2 stimulation was observed in TGF-β1-treated NHLFs compared with control cells without changes in HS-dependent FGF-2 binding or FGF-2·FR1c complex formation. To study the function of Sulf1, negative control or Sulf1-specific small interference RNA (siRNA)-transfected NHLFs were stimulated with TGF-β1. Enhanced Smad2/3 phosphorylation and elevated total Smad2 protein level were observed in Sulf1 siRNA-transfected cells and were accompanied by enhanced expression of -smooth muscle actin and fibronectin. In addition, Sulf1 siRNA transfection enhanced the anti-proliferative effect of TGF-β1. Finally Sulf1 expression was up-regulated in the lungs of mice treated with adenovirus encoding active TGF-β1. Taken together, our data indicate that Sulf1 is a TGF-β1-responsive gene both in vitro and in vivo and may function as a negative regulator of TGF-β1-induced fibrogenesis.

Received for publication, April 14, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL083480. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Postdoctoral Training Grant T32HL007973.

² To whom correspondence should be addressed: Dept. of Medicine, Pulmonary Section, SL-9, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699. Tel.: 504-988-2251; Fax: 504-988-2144; E-mail: jlasky{at}tulane.edu.

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				W. C. Lamanna, M.-A. Frese, M. Balleininger, and T. Dierks Sulf Loss Influences N-, 2-O-, and 6-O-Sulfation of Multiple Heparan Sulfate Proteoglycans and Modulates Fibroblast Growth Factor Signaling J. Biol. Chem., October 10, 2008; 283(41): 27724 - 27735. [Abstract] [Full Text] [PDF]