Researchers Link Master Regulator of Innate Immunity to the Hypoxic Response

Apr 23, 2008

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.

More than ten years ago, the Karin lab identified an enzyme called Iκβ kinase beta (IKKΒ) as the critical activator of NF-Iκβ. In this study, the UCSD researchers interfered with activation of NF-Iκβ 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-Iκβ, 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.

Previous work by UCSD co-contributors Victor Nizet, MD, professor of pediatrics and pharmacy and Randall S. Johnson, Ph.D., professor of biology, showed that bacterial infections -- which deplete infected cells and tissues of critical oxygen -- lead to accumulation of HIF-1α and activation of the hypoxic response.

"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-Iκβ," said Karin.

The NF-Iκβ and HIF-1α pathways have been extensively investigated as targets for new drug therapies. "Our new understanding of the interrelationship of NF-Iκβ and the hypoxic response provides clues toward new treatment strategies to boost the immune function of white blood cells in infected tissues." said Nizet. "Inhibition of the hypoxic response in macrophages might also limit inflammatory damage to brain tissues following stroke or cardiac arrest".

A unique series of mice with specific genetic alterations of HIF-1α or IKKΒ in various cells and tissues have been developed in the Karin and Johnson laboratories to continue these promising lines of investigation.

Source: University of California - San Diego

Explore further: Scientists discover RNA modifications in some unexpected places

add to favorites email to friend print save as pdf

Related Stories

Astronomers pinpoint 'Venus Zone' around stars

24 minutes ago

San Francisco State University astronomer Stephen Kane and a team of researchers presented today the definition of a "Venus Zone," the area around a star in which a planet is likely to exhibit the unlivable ...

History books becoming next fight in Texas schools

1 hour ago

The next ideological fight over new textbooks for Texas classrooms intensified Wednesday with critics lambasting history lessons that they say exaggerate the influence of Moses in American democracy and negatively portray ...

Amazon deforestation up 29 pc in 2013

1 hour ago

Deforestation in the Amazon rose 29 percent between August 2012 and July of last year to 5,891 square kilometers (2,275 square miles), Brazilian officials said Wednesday, posting an amended figure.

Recommended for you

Healthy humans make nice homes for viruses

3 hours ago

The same viruses that make us sick can take up residence in and on the human body without provoking a sneeze, cough or other troublesome symptom, according to new research at Washington University School ...

Meteorite that doomed dinosaurs remade forests

6 hours ago

The meteorite impact that spelled doom for the dinosaurs 66 million years ago decimated the evergreens among the flowering plants to a much greater extent than their deciduous peers, according to a study ...

New camera sheds light on mate choice of swordtail fish

8 hours ago

We have all seen a peacock show its extravagant, colorful tail feathers in courtship of a peahen. Now, a group of researchers have used a special camera developed by an engineer at Washington University in ...

User comments : 0