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STAT-1 Signaling in Human Lung Fibroblasts Is Induced by Vanadium Pentoxide through an IFN-β Autocrine Loop¹

Aurita Antao-Menezes^*, Elizabeth A. Turpin^*, Phillip C. Bost, Jessica P. Ryman-Rasmussen^*, and James C. Bonner^2,*,

^* The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709; and Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695

The inhalation of vanadium pentoxide (V₂O₅) results in bronchitis and airway fibrosis. The lung fibrotic response to V₂O₅ partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V₂O₅-induced STAT-1 phosphorylation in lung fibroblasts requires H₂O₂ and de novo protein synthesis. In this study, we identified IFN-β as the protein that mediates STAT-1 activation by V₂O₅ in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H₂O₂ that drive IFN-β gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-β as well as an inhibitor of JAK. V₂O₅ also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H₂O₂-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V₂O₅-induced IFN-β mRNA levels and CXCL10 expression. IFN- transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-β and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V₂O₅ injury.

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 This work was supported by The Long-Range Research Initiative of the American Chemistry Council and National Institutes of Health R21-ES015801-01.

² Address correspondence and reprint requests to Dr. James C. Bonner, North Carolina State University, Raleigh, NC 27695. E-mail address: james_bonner{at}ncsu.edu

³ Abbreviations used in this paper: EGF, epidermal growth factor; PDGF, platelet-derived growth factor; DPI, diphenyliodonium chloride; SFDM, serum-free defined medium; CM-H₂DCFDA, 5-(and-6)-chloromethyl-2',7'dichlorodihydrofluorescein diacetate, acetyl ester; RT, reverse transcriptase; ROS, reactive oxygen species; CTGF, connective tissue growth factor; HB-EGF, heparin-binding EGF.