Science and Reason: NF-κB and the hypoxic response

It seems as though the NF-κB transcription factor is turning up all over the place these days. Recent examples are in relation to the harmful effects of avian flu infection (here) and protection of cells from apoptosis due to radiation (here).

Now, the reason NF-κB is involved in the disasterous response of a person's lungs to the H5N1 virus is that it's a transcription factor affecting a number of immune system proteins. But a surprising recent discovery is that it also, independently of the immune system function, affects a cell's response to low oxygen conditions (hypoxia).

Researchers Link Master Regulator Of Innate Immunity To The Hypoxic Response

Survival of all animals depends on their ability to withstand microbial infections and adapt to fluctuations in oxygen concentrations. These abilities depend on two ancient, evolutionary gene expression responses called the innate immune response and the hypoxic response. In a new study published in the advanced online edition of the journal Nature on April 23, researchers at the University of California, San Diego School of Medicine reveal that a single protein is essential to both responses. This understanding may lead to new therapies to boost the body's immune function or to limit inflammatory damage in tissues deprived of oxygen.

The research, led by Michael Karin, Ph.D., professor of pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, shows that transcription factor NF kappa Β (NF-κΒ) -- previously known for its role as the master regulator of the innate immune response -- is also a critical regulator of the hypoxic response.

The hypoxic response consists of several survival measures that a cell takes to continue producing energy when its oxygen supply is curtailed. This happens, for example, in brain cells as a result of a stroke. One of the main parts of the response is switching energy production in the cell from the citric acid cycle to the less efficient process called glycolysis.

A family of transcription factors called, naturally enough, hypoxia-inducible factors regulate the hypoxic response. In particular, the master regulator is known as HIF-1α. Well, guess what, it turns out that HIF-1α is dependent on NF-κB.

More than ten years ago, the Karin lab identified an enzyme called IκΒ kinase beta (IKKβ) as the critical activator of NF-κΒ. In this study, the UCSD researchers interfered with activation of NF-κΒ by inactivating IKKβ in different cells and tissues of a laboratory mouse. When they examined how macrophages deficient in IKKβ responded to bacterial infections or oxygen deprivation, the researchers found that, in addition to the expected defect in activation of NF-κΒ, the macrophages also failed to accumulate HIF-1α, the master regulator of the hypoxic response. HIF-1α is normally accumulated in cells experiencing low ambient oxygen, or hypoxia; in turn, it activates several genes responsible for generating energy to allow cell survival. ...

"The hypoxic response is important in order for macrophages and other immune cells to kill and eliminate bacteria. The surprising result of the new study is the discovery that HIF-1α accumulation is dependent on activation of NF-κΒ," said Karin.