title: Overexpression of Sulf2 in idiopathic pulmonary fibrosis.
abstract: Previously, we have shown that heparan sulfate (HS) 6-O-endosulfatase 1 (Sulf1) is a transforming growth factor-β1 (TGF-β1)-responsive gene in normal human lung fibroblasts and functions as a negative feedback regulator of TGF-β1 and that TGF-β1 induces the expression of Sulf1 as well as that of the closely related Sulf2 in a murine model of pulmonary fibrosis. In this study, we focused on the role of Sulf2 in modulating TGF-β1 function and the development of pulmonary fibrosis. We found that Sulf2 mRNA was overexpressed in lung samples from human patients with idiopathic pulmonary fibrosis (IPF), and Sulf2 protein was specifically localized to the hyperplastic type II alveolar epithelial cells (AECs). In vitro, TGF-β1 induced the expression of Sulf2 with accompanied HS 6-O-desulfation in A549 cells, adenocarcinoma cells derived from the type II alveolar epithelium. Using small interference RNA to block Sulf2 expression, we observed a biphasic TGF-β1 response with early enhanced Smad activation, but eventually reduced TGF-β1 target gene expression in Sulf2 knockdown A549 cells compared with the control cells. To study the role of Sulf2 in normal type II AECs, we isolated primary type II cells from wild-type and Sulf2 knockout mice. We observed enhanced Smad activation as well as enhanced TGF-β1 target gene expression in Sulf2 knockout type II AECs compared with wild-type type II AECs. In conclusion, Sulf2 is overexpressed in IPF and may play a role in regulating TGF-β1 signaling in type II AECs.
authors: Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. xyue@lsuhsc.edu
authors: Xinping
authors: X
authors: Yue
authors: Jingning
authors: J
authors: Lu
authors: Linda
authors: L
authors: Auduong
authors: Mark D
authors: MD
authors: Sides
authors: Joseph A
authors: JA
authors: Lasky
mesh_terms: D000368:Aged; D056809:Alveolar Epithelial Cells / Q000201:enzymology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D061251:Primary Cell Culture; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013429:Sulfatases; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D006497:Heparan Sulfate; D051785:Smad Proteins; D013429:Sulfatases; D015238:Sulfotransferases; D053773:Transforming Growth Factor beta1; C470792:SULF2 protein, human
keywords: IPF; Sulf2; TGF-β1; fibrosis; heparan sulfate