HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling.

HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling. Research Abstract Details 

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HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling. Abstract Text:

Marzia Scortegagna,Christophe Cataisson,Rebecca J Martin,Daniel J Hicklin,Robert D Schreiber,Stuart H Yuspa,Jeffrey M Arbeit,Marzia Scortegagna,Christophe Cataisson,Rebecca J Martin,Daniel J Hicklin,Robert D Schreiber,Stuart H Yuspa,Jeffrey M Arbeit,

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 kappa B (NFkappaB) 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 NFkappaB activation was composed of 2 elements, IkappaB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFkappaB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFalpha) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFalpha 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 NFkappaB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.

HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling. Publishing Authors By Initials

M Scortegagna,C Cataisson,RJ Martin,DJ Hicklin,RD Schreiber,SH Yuspa,JM Arbeit,M Scortegagna,C Cataisson,RJ Martin,DJ Hicklin,RD Schreiber,SH Yuspa,JM Arbeit,

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HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Blood

VOLUME: 111

Page Numbers: 3343-54

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 16

MONTH: 01

YEAR: 2008

HIF-1{alpha} regulates epithelial inflammation by cell autonomous NF{kappa}B activation and paracrine stromal remodeling. Information

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LANGUAGE: eng

NlmUniqueID: 7603509

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