Sunday, April 20, 2008

Stimulating NF-κB for radiation protection

Can't resist posting about this, as it relates to one of my favorite transcription factors, NF-κB. (What' so great about NF-κB? I dunno. Maybe it's the catchy name. Besides, one of the systems it plays an important part in regulating is the immune system, especially with respect to inflammation. It's also important in the connection between inflammation and cancer. For more about it, check some other posts.)

NF-κB is actually a family of proteins, rather than a single one. It is also related to homologous proteins in a wide variety of animals, including fruit flies, sea urchins, anemones, and sponges – which is about as diverse a collection as there is in the animal department.

NF-κB is present in cells most of the time. That is, it doesn't need to await certain cell signaling events in order to be produced, which means it's always ready, albeit in an inactive state, to go to work when needed. For example, when a receptor (IL1R) for the immune system cytokine IL-1 fires up, the resulting signaling activates NF-κB that is already present.

Other receptors related to IL1R, called Toll-like receptors, can also lead to the activation of NF-κB. A specific Toll-like receptor in humans (TLR5) reacts to a bacterial protein called flagellin, which is normally found in the flagella of flagellated bacteria. That's not too surprising – this is one rather obvious way for the immune system to detect the presence of bacteria.

Now, another side of NF-κB is that it also regulates genes that control cell survival and proliferation. Specifically, it causes cells to resist apoptosis. Cancer cells take (unfair) advantage of this fact to upregulate NF-κB in order to promote their own nefarious proliferation. In particular, some cancer cells eventually become resistant to the radiation used in radiotherapy – precisely because those cells are the survivors of earlier radiotherapy.

All this background led some clever biologists to think that NF-κB could be useful in cases when one wants to protect cells from being killed by radiation – such as following a nuclear accident or explosion. It might also be helpful for astronauts on long space missions far from the Earth's protective magnetic shield against radiation.

Cancer researchers are looking for safe ways to inhibit NF-κB from protecting cancer cells. However, other biologists reasoned that doing the opposite might be a good way to protect healty cells from radiation. And further, perhaps exposing cells to flagellin might be a convenient way of activating NF-κB (instead of using an actual bacterial infection).

That line of thinking led to this:

New Drug Protects against Radiation Damage
A new drug may protect healthy tissue during cancer-killing radiation treatments or other exposures. Molecular geneticist Andrei Gudkov and colleagues report in Science this week that they protected mice from the cell-damaging effects of radiation by injecting them with a compound that helps cells resist apoptosis, or self-destruction.

Previous studies have found that cancerous cells use nuclear factor kappa-beta--a transcription factor, or protein that turns on or off a gene's protein-making ability--to outlive normal cells and grow out of control. But healthy cells in the gut switch on the same transcription factor when they interact with benign and beneficial bacteria that reside there. Specifically, the protein flagellin in some of the microorganisms' whiplike tails (which they use for propulsion) binds with a receptor on the gut cell and triggers the production of the transcription factor.

The experiment of injecting mice with flagellin and then exposing them to ordinarily lethal radiation seems to have been successful:
The injection not only protected the mice's cells but also toughened them against the effects of free radicals (molecules that can damage DNA or genetic material inside them) as well as beefed up the animal's immune systems. Mice without the injection died after the radiation treatments. "Never before has a single agent been capable of doing all three things together," [lead researcher Andrei] Gudkov says.

Further reading:

Bacteria tails could protect against 'dirty' bomb – news article in NewScientist

Drug Experiment Blocks Radiation Damage – AP news article – also here

Drug Bestows Radiation Resistance on Mice and Monkeys – news article in Science about the research.

An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models – technical paper in Science that reports the research.

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