Am. J. Respir. Cell Mol. Biol., Volume 22, Number 2, February, 2000 226-234

Regulation of Human 12/15-Lipoxygenase by Stat6-Dependent Transcription

Douglas J. Conrad and Min Lu

Section of Pulmonary and Critical Care, VA San Diego Healthcare System, the Veterans Medical Research Foundation; and the Department of Medicine, University of California San Diego, San Diego, California

Human 12/15-lipoxygenase is a lipid-peroxidating enzyme implicated in the pathophysiology of atherosclerosis and airway inflammation. Interleukin (IL)-4 specifically induces 12/15-lipoxygenase messenger RNA, protein, and enzymatic activity in primary cultures of human monocytes and airway epithelial cells. The induction of the human 12/15-lipoxygenase by IL-4 suggests that the signal transducer and activator of transcription (Stat)-6 protein is critical for its expression. Several putative Stat6 response elements are located in the proximal 1.8 kb of 12/15-lipoxygenase 5'-flanking region. In this study we use BEAS-2B human airway epithelial cells as a model to demonstrate the dependence of 12/15-lipoxygenase expression on the IL-4/Stat6 signal transduction pathway. Transient transfections of human 12/15-lipoxygenase promoter/luciferase reporter genes indicate that this induction occurs through direct transcriptional mechanisms mediated by a specific Stat6 response element located 952 base pairs upstream of the translational start codon. Using this Stat6 response element as a probe, electrophoretic mobility shift assays show an IL-4-dependent binding activity in nuclear extracts. Supershift assays confirm that Stat6 participates in this binding complex. These data indicate that the human 12/15-lipoxygenase gene is induced in airway epithelial cells through Stat6-dependent transcriptional mechanisms mediated by a specific Stat6 response element in the 5'-flanking region.

This article has been cited by other articles:

				J. Zhao, B. Maskrey, S. Balzar, K. Chibana, A. Mustovich, H. Hu, J. B. Trudeau, V. O'Donnell, and S. E. Wenzel Interleukin-13-induced MUC5AC Is Regulated by 15-Lipoxygenase 1 Pathway in Human Bronchial Epithelial Cells Am. J. Respir. Crit. Care Med., May 1, 2009; 179(9): 782 - 790. [Abstract] [Full Text] [PDF]

				X. Zuo, J. S. Morris, and I. Shureiqi Chromatin Modification Requirements for 15-Lipoxygenase-1 Transcriptional Reactivation in Colon Cancer Cells J. Biol. Chem., November 14, 2008; 283(46): 31341 - 31347. [Abstract] [Full Text] [PDF]

				I. Shureiqi, X. Zuo, R. Broaddus, Y. Wu, B. Guan, J. S. Morris, and S. M. Lippman The transcription factor GATA-6 is overexpressed in vivo and contributes to silencing 15-LOX-1 in vitro in human colon cancer FASEB J, March 1, 2007; 21(3): 743 - 753. [Abstract] [Full Text] [PDF]

				A. Bhattacharjee, B. Xu, D. A. Frank, G. M. Feldman, and M. K. Cathcart Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C {delta} and Tyrosine-Phosphorylated Stat3 J. Immunol., September 15, 2006; 177(6): 3771 - 3781. [Abstract] [Full Text] [PDF]

				B. Chen, S. Tsui, W. E. Boeglin, R. S. Douglas, A. R. Brash, and T. J. Smith Interleukin-4 Induces 15-Lipoxygenase-1 Expression in Human Orbital Fibroblasts from Patients with Graves Disease: EVIDENCE FOR ANATOMIC SITE-SELECTIVE ACTIONS OF Th2 CYTOKINES J. Biol. Chem., July 7, 2006; 281(27): 18296 - 18306. [Abstract] [Full Text] [PDF]

				Z. Chen, R. Lund, T. Aittokallio, M. Kosonen, O. Nevalainen, and R. Lahesmaa Identification of Novel IL-4/Stat6-Regulated Genes in T Lymphocytes J. Immunol., October 1, 2003; 171(7): 3627 - 3635. [Abstract] [Full Text] [PDF]

				X. Tang, N. Spitzbarth, H. Kuhn, P. Chaitidis, and W. B. Campbell Interleukin-13 Upregulates Vasodilatory 15-Lipoxygenase Eicosanoids in Rabbit Aorta Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1768 - 1774. [Abstract] [Full Text] [PDF]

				B. Xu, A. Bhattacharjee, B. Roy, H.-M. Xu, D. Anthony, D. A. Frank, G. M. Feldman, and M. K. Cathcart Interleukin-13 Induction of 15-Lipoxygenase Gene Expression Requires p38 Mitogen-Activated Protein Kinase-Mediated Serine 727 Phosphorylation of Stat1 and Stat3 Mol. Cell. Biol., June 1, 2003; 23(11): 3918 - 3928. [Abstract] [Full Text] [PDF]

				J. Wu, H. H. X. Xia, S. P. Tu, D. M. Fan, M. C. M. Lin, H. F. Kung, S. K. Lam, and B. C. Y. Wong 15-Lipoxygenase-1 mediates cyclooxygenase-2 inhibitor-induced apoptosis in gastric cancer Carcinogenesis, February 1, 2003; 24(2): 243 - 247. [Abstract] [Full Text] [PDF]

				J. S. Welch, L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, and C. K. Glass TH2 Cytokines and Allergic Challenge Induce Ym1 Expression in Macrophages by a STAT6-dependent Mechanism J. Biol. Chem., November 1, 2002; 277(45): 42821 - 42829. [Abstract] [Full Text] [PDF]

				B. Roy, A. Bhattacharjee, B. Xu, D. Ford, A. L. Maizel, and M. K. Cathcart IL-13 signal transduction in human monocytes: phosphorylation of receptor components, association with Jaks, and phosphorylation/activation of Stats J. Leukoc. Biol., September 1, 2002; 72(3): 580 - 589. [Abstract] [Full Text] [PDF]

				G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688. [Abstract] [Full Text] [PDF]