NFκB and HIF display synergistic behaviour during hypoxic inflammation

Ulrike Bruning, Susan F. Fitzpatrick, Till Frank, Marc Birtwistle, Cormac T. Taylor, Alex Cheong

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

The oxygen-sensitive transcription factor hypoxia inducible factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor nuclear factor kappa B (NFκB) during hypoxic inflammation. We describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel Gaussia princeps luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus, Gluc constructs under the control of either HIF or NFκB were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli, respectively. We also investigated the interactions between HIF and NFκB activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NFκB. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NFκB to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NFκB transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a co-ordinated role for both HIF and NFκB in the expression of COX-2 in hypoxic inflammation.

Original languageEnglish
Pages (from-to)1319-1329
Number of pages11
JournalCellular and Molecular Life Sciences
Volume69
Issue number8
DOIs
StatePublished - Apr 2012
Externally publishedYes

Keywords

  • Crosstalk
  • Hypoxia inducible factor
  • Inflammation
  • Mathematical modelling
  • NFκB
  • Transcription

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