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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3343-3354. Prepublished online as a Blood First Edition Paper on January 16, 2008; DOI 10.1182/blood-2007-10-115758. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-10-115758v1 111/7/3343    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Scortegagna, M. Articles by Arbeit, J. M. Search for Related Content PubMed PubMed Citation Articles by Scortegagna, M. Articles by Arbeit, J. M. Related Collections Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS HIF-1 regulates epithelial inflammation by cell autonomous NFB activation and paracrine stromal remodeling Marzia Scortegagna1, Christophe Cataisson2, Rebecca J. Martin1, Daniel J. Hicklin3, Robert D. Schreiber4,5, Stuart H. Yuspa2, and Jeffrey M. Arbeit1,5,6 1 Department of Surgery, Division of Urology, Washington University School of Medicine, St Louis, MO; 2 Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Reseach National Cancer Institute, Bethesda, MD; 3 ImClone Systems, New York, NY; and 4 Center for Immunology, Department of Pathology and Immunology, 5 Siteman Cancer Center, and 6 Program in Cell Biology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St Louis, MO Hypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor B (NFB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFB activation was composed of 2 elements, IB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNF) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNF immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Tacchini, E. Gammella, C. De Ponti, S. Recalcati, and G. Cairo Role of HIF-1 and NF-{kappa}B Transcription Factors in the Modulation of Transferrin Receptor by Inflammatory and Anti-inflammatory Signals J. Biol. Chem., July 25, 2008; 283(30): 20674 - 20686. [Abstract] [Full Text] [PDF]

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