New Approach to Thwarting Inflammation

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New Approach to Thwarting Inflammation

" I think that the remarkable anti-inflammatory effect that we achieved

validates the approach of relieving inflammation by interfering with the

activation of NF-kB alone, " said HHMI investigator Sankar Ghosh.

September 1, 2000- Medical Institute (HHMI) researchers have

discovered a way to shut down the inflammatory response in cells that spares

related mechanisms that cells need in order to function properly. Their

experiments have demonstrated that such treatment relieves inflammation in mice

with surprising effectiveness.

In an article published in the September 1, 2000, issue of Science, HHMI

investigator Sankar Ghosh and his colleagues at Yale University report that they

have found a way to short circuit NF-kB, a central coordinator of the cell's

inflammatory response. When NF-kB is triggered by an external chemical signal,

NF-kB sets in motion the gene expression machinery that drives inflammation.

" It has become clear over the years that NF-kB plays a crucial, evolutionarily

conserved role in the cell's response for getting rid of pathogens, " said Ghosh.

" As a byproduct of this immune response, inflammation can get out of control and

cause pathogenic states. We now know that many diseases that at first glance

don't seem to have much in common actually have inflammation as an underlying

reason for their pathology. " Alzheimer's disease, for example, might well

involve inflammatory responses that damage brain tissue, Ghosh noted.

The most widely used anti-inflammatory drugs, including salicylates such as

aspirin, and steroids, inhibit NF-kB to some extent, but they can also have

severe side effects. The great need for more precise inhibitors of inflammation

prompted Ghosh and his colleagues to look at ways to block inflammation by

interfering with NF-kB.

The scientists knew that in unstimulated cells NF-kB remains in the cell's

cytoplasm attached to inhibitory proteins known as IkBs. When an external

inflammatory signal affects the cell, the IkB-kinase (IKK) complex-which

consists of a pair of catalytic enzymes-is activated and phosphorylates the IkB

proteins. The phosphorylated IkB is then rapidly degraded, thus freeing NF-kB to

trigger the inflammatory process.

While the majority of research on blocking the inflammatory process has focused

on blocking the catalytic activity of the IKK complex itself, Ghosh and his

colleagues chose another route. " By themselves, the enzymes of the IKK complex

don't respond to signals, " explained Ghosh. " Each enzyme needs a regulatory

subunit protein called NEMO, and it has been shown that when NEMO is knocked out

in mice, NF-kB becomes unresponsive to signaling. "

In a series of biochemical experiments, Ghosh and his colleagues sought to

identify the minimal region of the IKK enzymes that interacted with NEMO. " We

were quite surprised to find that a very small region of the IKK enzymes seemed

to be completely responsible for interacting with NEMO, " said Ghosh. The

scientists called the region the NEMO-binding domain (NBD).

" We reasoned that if the NBD was such a small region, then maybe we could use it

as a way to disrupt the whole IKK complex and prevent it from forming, " said

Ghosh. Sure enough, when the scientists synthesized a small peptide that

mimicked the NBD and put it into cells, they discovered that NF-kB activation

was blocked significantly.

" Then we raised the stakes, " said Ghosh. " We decided to see if this blocking

method would work in vivo in animals. " The scientists used the NBD peptide to

attempt to block inflammation in two mouse models where chemicals are used to

induce inflammation artificially.

" In both models, when we injected our peptide, we observed quite a dramatic

amelioration of the inflammatory process, " said Ghosh. " I think that the

remarkable anti-inflammatory effect that we achieved validates the approach of

relieving inflammation by interfering with the activation of NF-kB alone. This

approach should become a major focus of future research. "

Ghosh also said that blocking the activation of NF-kB by external inflammatory

factors quite likely spares the basal activity of the NF-kB machinery that

operates via a different pathway, and which cells need for normal function.

" One of the concerns that has been raised about inhibiting NF-kB, is that NF-kB

also has some beneficial effects, such as helping cells survive apoptosis, or

programmed cell death, " said Ghosh.

Ghosh and his colleagues are planning further studies to investigate the

NEMO-IKK interaction. They are going to test the NBD peptide on mouse models of

asthma and other diseases that involve inflammation. They also hope to initiate

collaborations with pharmaceutical companies to develop mimics of the NBD

peptide that can be used as precise inhibitors of inflammation.

Photo: Yale University

http://www.hhmi.org/news/ghosh.html