Sci. Aging Knowl. Environ., 9 April 2003
Vol. 2003, Issue 14, p. nw54
[DOI: 10.1126/sageke.2003.14.nw54]


Your Intestines or Your Life

Inflammation-producing protein saves suicidal cells but provokes organ failure

Mitch Leslie;2003/14/nw54

Key Words: multiple organ dysfunction syndrome • reperfusion • tumor necrosis factor

A protein suspected of spurring potentially fatal inflammation also does good deeds, according to new research. The study confirms that the protein triggers potentially lethal inflammation--but also reveals that it prevents cells from killing themselves. The work raises the possibility that anti-inflammatory drugs under development that squelch the protein's activities will elicit punishing side effects.

Inflammation helps the body heal, but if it's prolonged or pervasive, it can be deadly. For example, surgery, severe wounds, and raging infections can instigate widespread, swift inflammation that can damage the lungs and even cause organs to shut down. Organ failure kills up to 50% of its victims, even with the best medical care. Although chronic inflammation is not as dramatic, it underlies conditions such as rheumatoid arthritis and colitis as well as age-related killers such as heart disease. Scientists suspect that the protein NF-{kappa}B drives acute and chronic inflammation. Injuries, infections, and inflammatory diseases crank up the amount of activated NF-{kappa}B tissue of people with inflammatory diseases. Moreover, the protein turns on genes that spur inflammation. However, uncertainty lingers because researchers can't shut down NF-{kappa}B in mice and observe the effects. The protein comes in multiple varieties, and disrupting the genes for all of them isn't practical. "Everybody believes that NF-{kappa}B plays a critical role in inflammation, but nobody's been able to prove it," says molecular biologist Michael Karin of the University of California, San Diego.

To nail down NF-{kappa}B's function, Karin and colleagues meddled with IKK, a protein that rouses most of the forms of NF-{kappa}B. Completely disabling the mouse version of IKK throughout the body kills the animals before birth, so the researchers engineered only the intestinal cells of mice to lack a key part of IKK, thus curtailing NF-{kappa}B production in those cells. The researchers then spurred acute inflammation by temporarily closing off an artery that feeds the small intestine. The lungs of the control mice filled with fluid, and the rodents swiftly died of organ failure. Mice with disabled IKK suffered neither problem, but large numbers of intestinal cells killed themselves through a process called apoptosis. The results suggest that NF-{kappa}B orchestrates this devastating form of inflammation, says Karin, but also stops cells from committing suicide. The researchers speculate that loss of these cells could allow bacteria to infiltrate the body through the intestinal lining, possibly leading to severe infections.

The study is significant because it exposes the two faces of NF-{kappa}B, says molecular biologist Thomas Gilmore of Boston University. "The body has adapted this system [IKK and NF-{kappa}B] for two functions that are antagonistic," he says. Pharmaceutical companies have been racing to design drugs that block IKK or NF-{kappa}B and tame inflammation. The evidence of NF-{kappa}B's dual nature should warn drug designers that shutting down either molecule could spur grave side effects by unleashing apoptosis, he says. However, says Karin, the study doesn't prove that disastrous consequences are inevitable. We need careful work to determine when short-circuiting the inflammation pathway will lead to serious problems and to show how to bring out the positive side of NF-{kappa}B's split personality.

--Mitch Leslie

April 9, 2003
  1. L.-W. Chen et al., The two faces of IKK and NF-{kappa}B inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat. Med., 7 April 2003 [e-pub ahead of print]. [Abstract/Full Text]
Citation: M. Leslie, Your Intestines or Your Life. Sci. SAGE KE 2003, nw54 (9 April 2003);2003/14/nw54

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