Molecular immunologyNov 2, 2013

Control of oxygen-sensing proteins in human immune cells during long-term low oxygen levels

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

The study reveals that HIF-2α protein expression increases significantly under sustained hypoxia, while HIF-1α decreases dramatically.

Both HIF-1α and HIF-2α protein levels rise in response to hypoxia due to protein stabilization.
Sustained hypoxia leads to a marked increase in HIF-2α expression contrasted by a significant decrease in HIF-1α levels.
The long-term reduction of HIF-1α is associated with decreased mRNA levels.
A natural antisense transcript, ahif, is strongly induced by hypoxia and rapidly degraded after reoxygenation.
The HIF-system itself appears to mediate the targeted regulation of ahif, which in turn affects HIF-1α expression and the expression of the HIF-target gene Enolase-2.

Simplified

Macrophages are often associated to pathophysiological processes and were found at hypoxic areas. However, cell adaption greatly depends on hypoxia-inducible factors (HIF). Activation of these transcription factors is induced by heterodimerization of an α-(HIF-1α, -2α, -3α) and HIF-1β subunit. The main regulatory pathway is represented by α-subunit stability. Beside, little is known about the exact mechanisms of fine-tuning in Hif-regulation. The present study characterizes the hypoxia-induced regulation of HIF-1α and -2α in human macrophages. The hypoxic increase of both subunits is initially mediated by protein stabilization. Sustained hypoxia caused a distinct regulation of HIF-1α and -2α. The striking increase of HIF-2α protein expression was contrasted by a dramatic decrease of HIF-1α. The long-term downregulation of HIF-1α is due to downregulation of its mRNA. This decrease was accompanied by increased expression of ahif, a natural cis-antisense transcript of HIF-1α. The ahif-transcript was strongly inducible by hypoxia and rapidly degraded under reoxygenation. Using an adenoviral overexpression and siRNA silencing approach revealed that the targeted regulation of ahif is mediated by the HIF-system itself. Furthermore it could be shown that ahif indeed is able to modulate the hypoxic expression of HIF-1α and influences the expression of the HIF-target gene Enolase-2. Taken together, this study characterizes a new regulation process of the HIF-transcription factor-system in human macrophages under hypoxia. For the first time evidence is provided that ahif is regulated by the HIF-system and influences HIF-1α expression in primary human macrophages.

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Control of oxygen-sensing proteins in human immune cells during long-term low oxygen levels

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