Published online 16 July 2007 | Nature | doi:10.1038/news070716-1

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Immune protein makes the body clock turn down a notch.

Sniffling, sneezing, and feeling sleepy can go hand in hand. Getty

Getting sick often means getting tired too. Now researchers have tracked down how the chemical responsible for such drowsiness works.

The culprit is a small protein called tumour necrosis factor alpha (TNF-alpha), named for its anti-tumour properties. This compound was known to trigger inflammation in response to infection and some chronic diseases such as rheumatoid arthritis and multiple sclerosis. And it was known to be linked — somehow — to fatigue. Cancer patients treated with TNF-alpha sometimes report severe lethargy, for example. And patients with a sleep disorder called sleep apnea sometimes report less daytime sleepiness after receiving a drug that interferes with TNF-alpha.

But precisely how the protein was affecting sleep habits was unclear.

Thomas Birchler, an immunologist at the University Hospital of Zurich in Switzerland, and his colleagues administered TNF-alpha to mice and then monitored the expression of genes involved in the biological clock, the internal timekeeper that tells us when to go to sleep and when to wake up.

They found that the genes were expressed in their normal rhythm, rising and falling at designated points during the day. But the overall level of expression of some of these genes was reduced in mice that received the drug. "The oscillations were still in rhythm," says Birchler. "But the output of the clock genes was much reduced."

Mice given TNF-alpha were also less active and spent less time on their running wheels or walking around their cages — as if they were tired.

"This opens up an area that should be fertile ground for research," says immunologist Rodney Johnson of the University of Illinois, Urbana-Champaign. "We've known for years now that TNF-alpha induces changes in sleep patterns. This is the beginning of connecting it with genes involved in circadian rhythms."

Sufficient sleep is crucial for a healthy immune system and may help speed up recovery. "There is evidence that sleep helps fight against infections," says Birchler, "and from an evolutionary point of view, fatigue can prevent the infected individual from joining in social activities, and keep the infection from spreading through the whole population."

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But although it may be beneficial in the short term, fatigue can be debilitating in patients with chronic inflammatory diseases. "The fatigue and altered sleep that was maybe initially beneficial can actually become pathological," says Johnson. "Too much of a good thing is not always a good thing."

Interfering with TNF-alpha?can help such patients with chronic inflammatory conditions to avoid chronic fatigue. But the treatment can also weaken the immune system and promote infection and the development of autoimmune disorders. So researchers are keen to understand the mechanisms behind drowsiness, and perhaps find better ways to beat it back.

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