Inhibitory switch found for master regulator of inflammation, Gladstone reseachers report

Often called the “master regulator,” NF-kB is a protein that controls a whole
host of important bodily functions including the key inflammatory and immune
responses. Researchers at the Gladstone Institute of Virology and Immunology
have now discovered a new pathway by which the cell regulates the activity of
NF-kB, setting the stage for new therapeutic approaches.

Published in the August 31, 2001 issue of Science, the study unveils
significant information about the much-studied NF-kB, which is central to many
biological processes. NF-kB is known to be a transcription factor, a protein
that jumpstarts the production of other proteins that go on to trigger
inflammatory and immune responses. In order for NF-kB to be active, it must
enter the nucleus where the DNA, the genetic blueprint for proteins, is
located.

“These findings reveal a previously unknown mechanism by which this powerful
transcription factor is regulated,” said Warner C. Greene, MD, PhD, senior
author of the paper and director of the Gladstone Institute of Virology and
Immunology.

The Gladstone scientists have shown that a chemical reaction called
acetylation, whereby an acetyl molecule is attached to NF-kB, determines if
NF-kB is active or not. When acetylated, NF-kB is active and resistant to the
effects of an inhibitory protein called IkBa. However, once an enzyme called

HDAC3 deacetylates NF-kB, IkBa readily binds to NF-kB and causes the
transcription factor to move out of the nucleus into the cytoplasm.
HDAC3, then, becomes the “intranuclear molecular switch” that turns off the
biological processes triggered by NF-kB. With more study, developing drugs that
selectively promote the deaceytlation of NF-kB could be useful in treating a
myriad of diseases. These include rheumatoid arthritis and chronic inflammatory
bowel disease.

“These agents could form an exciting new class of anti-inflammatory drugs,”
Greene said.

The need for them is clear. Glucocorticoids, the most common anti-inflammatory
drugs in clinical use today, are plagued with serious side effects, Greene
said.

Immunosuppressive drugs, like cyclosporin A, have serious side effects too.
Drugs based on the NF-kB deacetylation could help give an alternative to
patients who have undergone organ transplants or who are suffering from
systemic lupus erythematosus.

“We clearly need better anti-inflammatory drugs and superior approaches to
immune suppression in the clinic,” said Greene, who is also a UCSF professor of
medicine, microbiology and immunology. Since, NF-kB also plays a key role in
the growth of many types of human cancer, these drugs might also exhibit
anti-cancer activity.

Greene and his colleagues showed many years ago that when NF-kB was activated
IkBa would degrade in the cytoplasm. However, more IkBa would soon be produced
as NF-kB entered the nucleus and triggered the production of its own inhibitor,
IkBa the current findings unveil how the cycle of acetylation and deacetylation
controls the ability of these newly synthesized IkBa molecules to inhibit
NF-kB. As an inhibitor, IkBa then limits the time in which NF-kB is able to
act.

Other contributors to this study include Lin-feng Chen, PhD, postdoctoral
fellow in Greene’s laboratory; Gladstone research associate Wolfgang Fischle,
MS; and Gladstone senior investigator Eric Verdin, MD, UCSF professor of
medicine. This study was funded by the Gladstone Institute of Virology and
Immunology.

The Gladstone Institute of Virology and Immunology is one of three research
institutes that comprise The J. David Gladstone Institutes, a private
biomedical research institution affiliated with UCSF. The institution is named
for a prominent real estate developer who died in 1971. His will created a
testamentary trust that reflects his long-standing personal interest in medical
education and research.

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