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Patients with fibrotic lung disorders have very low levels of GSH in their alveolar epithelial lining fluid (ELF), whereas transforming growth factor (TGF)-\u03b2 is overexpressed in their alveolar epithelial cells. We observed that TGF-\u03b21 increased susceptibility of the human alveolar epithelial cell line A549 to H2O2-mediated cytotoxicity (P &amp;lt; 0.05), decreased the activities of the antioxidant enzymes glutathione reductase and catalase by 31%, and markedly decreased GSH content in A549 cells (P &amp;lt; 0.01). GSH depletion was associated with an equivalent decrease in the activity of the rate-limiting enzyme in GSH synthesis, \u03b3-glutamylcysteine synthetase (\u03b3-GCS) (P &amp;lt; 0.01). Western blot analysis confirmed that the loss of \u03b3-GCS activity was associated with a marked decrease in \u03b3-GCS heavy subunit (\u03b3-GCShs) protein. TGF-\u03b21 suppressed the steady-state level of messenger RNA (mRNA) for the \u03b3-GCShs gene, with a maximal effect at 24 h. The half-life of \u03b3-GCShs mRNA was not affected by TGF-\u03b21, but transcription of the gene was downregulated as determined with nuclear run-on assays. Our findings indicate for the first time that TGF-\u03b21 is a potent inhibitor of GSH synthesis in human lung epithelial cells, and that the inhibition is mediated, at least in part, by a transcriptional effect on the gene encoding \u03b3-GCShs. Regulation of \u03b3-GCShs gene expression by TGF-\u03b21 is likely to play an important role in lower respiratory tract GSH homeostasis, and may represent a novel target for therapeutic efforts in lung fibrosis.<\/jats:p>","DOI":"10.1165\/ajrcmb.17.5.2833","type":"journal-article","created":{"date-parts":[[2013,4,3]],"date-time":"2013-04-03T22:25:53Z","timestamp":1365027953000},"page":"599-607","source":"Crossref","is-referenced-by-count":121,"title":["Transforming Growth Factor-\u03b21 Is a Potent Inhibitor of Glutathione Synthesis in the Lung Epithelial Cell Line A549: Transcriptional Effect on the GSH Rate-limiting Enzyme \u03b3-Glutamylcysteine Synthetase"],"prefix":"10.1093","volume":"17","author":[{"given":"Karim","family":"Arsalane","sequence":"first","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire M.","family":"Dubois","sequence":"additional","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Muanza","sequence":"additional","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"B\u00e9gin","sequence":"additional","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Boudreau","sequence":"additional","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Asselin","sequence":"additional","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 M.","family":"Cantin","sequence":"additional","affiliation":[{"name":"Unit of Pulmonary Research, Department of Medicine; Service of Immunology, Department of Pediatrics; and Department of Anatomy and Cell Biology, Universit\u00e9 of Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[1997,11,1]]},"reference":[{"key":"2026030700210829200_B1","doi-asserted-by":"crossref","first-page":"769","DOI":"10.7326\/0003-4819-85-6-769","article-title":"Idiopathic pulmonary fibrosis: clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects.","volume":"85","author":"Crystal","year":"1976","journal-title":"Ann. 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