Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of β2integrin gene expression

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Abstract
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 β2, but not β1, integrins. Analysis of β2integrin 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 β2integrin mRNA and proteinex vivo. Furthermore, murine β2integrin mRNA was found to be significantly induced during hypoxiain 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 β2integrin heterodimer. HIF-1 binding was demonstratedin 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 β2integrin expression and function by transcriptional mechanisms dependent upon HIF-1.