Identification of Purα as a New Hypoxia Response Factor Responsible for Coordinated Induction of the β2 Integrin Family

Abstract

Central to the process of inflammation are hypoxic conditions that lead to the binding of circulating leukocytes to the endothelium. We have previously shown that such binding is mediated by monocytes being able to directly sense hypoxic conditions and respond by inducing their surface expression of the β2 integrin family of adhesion molecules. In this study, we show that coordinated induction of the β2 integrins during direct hypoxia-sensing occurs through transcriptional activation of each of the genes by which they are encoded. Certain of the molecular mechanisms that mediate this activation in transcription are dependent upon hypoxia-inducible factor-1 (HIF-1), whereas others are HIF-1 independent. In search of these HIF-1-independent mechanisms, we identified Purα as a new hypoxia-response factor. Binding of Purα to the HIF-1-independent β2 integrin promoters is induced by hypoxia and mutagenesis of these Purα-binding sites almost completely abolishes the ability of the promoters to respond to hypoxic conditions. Additional studies using siRNA directed against Purα also revealed a loss in the hypoxic response of the β2 integrin promoters. Taken together, our findings demonstrate that hypoxia induces a coordinated up-regulation in β2 integrin expression that is dependent upon transcriptional mechanisms mediated by HIF-1 and Purα.