Master Regulator Of Innate Immunity Linked 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 B (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 (IKKB) as the critical activator of NF-Iκβ. In this study,
the UCSD researchers interfered with activation of NF-Iκβ by
inactivating IKKB in different cells and tissues of a laboratory
mouse. When they examined how macrophages deficient in IKKB 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
IKKB in various cells and tissues have been developed in the Karin and
Johnson laboratories to continue these promising lines of
investigation.

----------------------------
Article adapted by Medical News Today from original press release.
----------------------------

Additional contributors to the paper, all at UCSD, include Gabriel G.
Haddad, M.D., professor of pediatrics; Katerina Akassoglou, Ph.D.,
UCSD assistant professor of pharmacology; and postgraduate researchers
Jodi Rius, Ph.D. and Monica Guma, Ph.D., Laboratory of Gene Regulation
and Signal Transduction, Departments of Pharmacology and Pathology;
Christian Schachtrup, Ph.D., Department of Pharmacology, and Annelies
S. Zinkernagel, M.D., Department of Pediatrics.

The study was funded in part by grants from the National Institutes of
Health, with additional support from the Spanish Ministry of Education
and Science. Michael Karin is an American Cancer Society Research
Professor.

Source: Debra Kain
University of California - San Diego

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