Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1β (IL-1β) in astrocyte cultures

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of HIF-1α and HIF-1β subunits and involved in the regulation of gene expression in adaptive response to hypoxia. This study reports that the inflammatory cytokine interleukin-1β (IL-1β) shares common features of other known HIF-1α-regulated genes. Both human and mouse IL-1β genes carry multiple HIF-1-binding sites in their promoter regions and are up-regulated by hypoxia and CoCl2 in human and mouse astrocytes in parallel with up-regulation of HIF-1α mRNA and protein. Inhibition of HIF-1α degradation by proteasome inhibitor, MG-132, potentiated hypoxia-induced IL-1β release from human astrocytes, and this response was blocked in the presence of CdCl2. Mouse astrocytes with Hif1α+/− genotype demonstrated attenuated up-regulation of both HIF-1α and IL-1β by hypoxia and CoCl2. Mutation of HIF-1-binding sites in the IL-1β promoter abolished hypoxia-induced transactivation of the reporter gene transfected into human astrocytes. Similarly, HIF-1 binding “decoy” oligonuleotide transfected into astrocytes inhibited both hypoxia-induced transactivation of the HIF-1 reporter gene and IL-1β secretion from transfected astrocytes. Collectively, the evidence suggests that the transcriptional activation of IL-1β in astrocytes exposed to hypoxia occurs via HIF-1.