NF-κB in hypoxia: And now for something completely different

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The transcription factor NF-κB induces the expression of HIF-1α, providing a link between innate immunity and the hypoxic response.

During bacterial infection, induction of angiogenic factors such as hypoxia-inducible transcription factor-1 (HIF-1α), and immune response factors such as nuclear factor-κB (NF-κB) prevents hypoxia and cell death. Previous studies indicated that IκB kinase (IKK-β) — which regulates NF-κB activity — and HIF-1α were both post-translationally degraded by oxygen-dependent prolyl hydroxylases (PHDs) under normoxic conditions, suggesting a link between hypoxia and the innate immune response. In Nature, Michael Karin and colleagues now provide evidence for a novel intersection between these two pathways, as they show that NF-κB induces HIF-1α transcription in vivo.

The relationship between the NF-κB and HIF-1α pathways was examined in bone marrow-derived macrophages (BMDMs) from IKK-β-deficient mice. These BMDMs had reduced basal levels of Hif1α mRNA, and HIF-1α and its target genes were not induced during hypoxia or bacterial infection. When evaluated in vivo, hypoxia induced Hif1α mRNA in the livers of wild-type, but not IKK-β-deficient mice. Depletion of IKK-β also correlated with a reduction in both HIF-1α protein and vascular endothelial growth factor (Vegf) mRNA.

One possible explanation for this observation is that NF-κB is required for Hif1α transcription. Indeed, hypoxia promoted nuclear accumulation of the NF-κB RelA subunit and subsequent accumulation of HIF-1α in wild-type macrophages, but not IKK-β-deficient BMDMs. Furthermore, RelA bound directly to the Hif1α promoter. RelA was required for Hif1α induction in fibroblasts under normoxic conditions, suggesting that NF-κB also facilitates basal Hif1α transcription.

Lipopolysaccharide (LPS)-mediated induction of NF-κB in hypoxic cells induced Hif1α promoter activity, leading to accumulation of HIF-1α protein and increased Vegf expression. In normoxic cells, however, LPS treatment caused accumulation of Hif1α mRNA, but not protein, which indicates that accumulation of HIF-1α protein in hypoxic conditions is nonetheless dependent on the concomitant inhibition of PHDs.

Previous studies suggested that HIF-1α induction during hypoxia is predominately achieved through post-transcriptional mechanisms — namely, through the inhibition of PHD-mediated degradation. Karin and colleagues now reveal that hypoxia also stimulates NF-κB-mediated transcription of Hif1α mRNA in vivo. It is interesting to note that NF-κB is necessary for Hif1α transcription in normal and hypoxic conditions. However, post-transcriptional regulation of HIF-1α protein is essential for the hypoxic response, as HIF-1α protein was found to accumulate only in hypoxic conditions. Together, these data document a new role for IKK-β–NF-κB signaling in the response to bacterial infection and hypoxia, as it not only induces cytokines and antimicrobial peptides, but also upregulates pro-angiogenic factors to maintain tissue homeostasis.

Emily J. Chenette
Signaling Gateway

Reference

Rius J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807-811 (2008) | Article | PubMed |