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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 2, 2007 Accepted January 11, 2008 HIF-1 regulates epithelial inflammation by cell autonomous NFB activation and paracrine stromal remodeling Marzia Scortegagna, Christophe Cataisson, Rebecca J. Martin, Daniel J. Hicklin, Robert D. Schreiber, Stuart H. Yuspa, and Jeffrey M. Arbeit* Department of Surgery, Division of Urology, Washington University School of Medicine, St. Louis, MO, United States Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States ImClone Systems Incorporated, New York, NY, United States Center for Immunology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States * Corresponding author; email: arbeitj{at}msnotes.wustl.edu. 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 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 TPA challenge. HIF-1 induced NFB activation was composed of two 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 TNF constitutively upregulated and further increased following TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNF immunodepletion each abrogated TPA-induced inflammation, while blockade of either VEGF or PlGF signaling did not affect transgenic inflammatory hyperresponsiveness. 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: H.-M. Lee, J.-M. Yuk, D.-M. Shin, C.-S. Yang, K.-K. Kim, D.-K. Choi, Z.-L. Liang, J.-M. Kim, B. H. Jeon, C. D. Kim, et al. Apurinic/Apyrimidinic Endonuclease 1 Is a Key Modulator of Keratinocyte Inflammatory Responses J. Immunol., November 15, 2009; 183(10): 6839 - 6848. [Abstract] [Full Text] [PDF] J. F. Garvey, C. T. Taylor, and W. T. McNicholas Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation Eur. Respir. J., May 1, 2009; 33(5): 1195 - 1205. [Abstract] [Full Text] [PDF] M. Scortegagna, R. J. Martin, R. D. Kladney, R. G. Neumann, and J. M. Arbeit Hypoxia-Inducible Factor-1{alpha} Suppresses Squamous Carcinogenic Progression and Epithelial-Mesenchymal Transition Cancer Res., March 15, 2009; 69(6): 2638 - 2646. [Abstract] [Full Text] [PDF] C. T. Taylor Interdependent roles for hypoxia inducible factor and nuclear factor-{kappa}B in hypoxic inflammation J. Physiol., September 1, 2008; 586(17): 4055 - 4059. [Abstract] [Full Text] [PDF] 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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