Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression.

Journal Article

Inflammatory responses are associated with significant changes in tissue metabolism. In particular, metabolic shifts during inflammation can result in significant tissue hypoxia, with resultant induction of hypoxia-responsive genes. Given this association, we hypothesized that leukocyte functional responses are influenced by hypoxia. Initial experiments revealed that exposure of the promonocytic cell line U937 to hypoxia resulted in increased adhesion to activated endothelia. Such increases were transcription-dependent and were blocked by antibodies directed against beta2, but not beta1, integrins. Analysis of beta2 integrin mRNA and protein in U937 cells revealed a 5- to 6-fold increase with hypoxia. Extension of this analysis to hypoxic human whole blood revealed prominent induction of beta2 integrin mRNA and protein ex vivo. Furthermore, murine beta2 integrin mRNA was found to be significantly induced during hypoxia in vivo. Subsequent studies identified a binding site for hypoxia-inducible factor 1 (HIF-1) in the CD18 gene. This gene encodes the subunit common to all four known types of beta2 integrin heterodimer. HIF-1 binding was demonstrated in vivo, and mutational analysis of the HIF-1 site within the CD18 promoter resulted in a loss of hypoxia inducibility. Taken together, these results demonstrate that hypoxia induces leukocyte beta2 integrin expression and function by transcriptional mechanisms dependent upon HIF-1.

Full Text

Duke Authors

Cited Authors

  • Kong, T; Eltzschig, HK; Karhausen, J; Colgan, SP; Shelley, CS

Published Date

  • July 13, 2004

Published In

Volume / Issue

  • 101 / 28

Start / End Page

  • 10440 - 10445

PubMed ID

  • 15235127

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0401339101

Language

  • eng

Conference Location

  • United States