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TheScientist

MAGAZIN OF THE LIFE SCIENCE

By Melissa Lee Phillips

 

http://www.the-scientist.com/news/home/53380/

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NEWS

 

Immune system, circadian clock linked

 

Infectious and autoimmune diseases may promote sleep by down-regulating

circadian gene expression

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[Published 17th July 2007 10:20 AM GMT]

 

 

The immune system alters mammalian circadian clock gene expression, perhaps

explaining why fatigue accompanies some infections and autoimmune diseases,

according to a study in this week's Proceedings of the National Academy of

Sciences.

The authors found that a protein involved in mammalian immunity interferes

with circadian clock gene expression and promotes sleep in mice.

 

" The study certainly provides a framework within which to address the

question of how immunomodulators affect both the timing and the quantity or

quality

of sleep, " said Mark Opp of the University of Michigan in Ann Arbor, who was

not involved in the

study.

 

The immune response to microbial infection activates pro-inflammatory

molecules such as tumor necrosis factor alpha (TNF-a). Previous work has

suggested

that TNF-a causes lethargy and fatigue in people with cancer, rheumatoid

arthritis, and sleep apnea. Animal studies have also shown that TNF-a enhances

sleep, but the mechanism has remained unknown.

 

To see if TNF-a directly regulates circadian oscillations, researchers led by

Gionata Cavadini of University Hospital Zurich in Switzerland analyzed

TNF-a's effects on expression of circadian clock genes. " There's very little

known

about how [immune response] is related to circadian rhythms, " said James

Krueger of Washington State University in Pullman, who was not involved in the

work.

 

The central circadian oscillator in mammals lies in the suprachiasmatic

nucleus (SCN) of the hypothalamus, but other body cells also contain peripheral

oscillators that keep their own rhythms. Interacting loops of gene transcription

and translation form a negative feedback system that generates the 24-hour

mammalian clock.

 

The researchers first found that, in culture, TNF-a suppresses the expression

of three circadian clock genes called Period, and the expression of three

transcription factors they controlled by clock genes. TNF-a only affected the

genes' expression levels; it

did not affect the times at which they were expressed.

 

Other work has shown that activation of Period genes as well as the

transcription factors depends on a specific DNA sequence - called an E-box -

lying

upstream of these genes. Transcription factors bind to the E-box sequence to

initiate these genes'

transcription.

 

When Cavadini and her colleagues mutated the E-box sequence, administering

TNF-a did not suppress transcription. Conversely, TNF-a did not activate

circadian clock genes whose expression does not depend on an E-box sequence.

 

Their results suggest that TNF-a affects only clock genes that contain an

E-box and that the reduced activity of these genes affects sleep regulation,

co-author Thomas Birchler, also of University Hospital Zurich, told The

Scientist

in an Email.

 

When the researchers tested the effects of TNF-a in live mice, they found

that animals treated with the cytokine kept normal cycles -- sleeping during the

day and becoming active at night - but they moved less and rested more during

their active periods

than did untreated mice. These results paralleled in vitro findings showing

that TNF-a changes clock genes' expression levels but not timing, the authors

say. Also, as in the in vitro studies, TNF-a down-regulated expression of

Period and the three clock-controlled transcription factors in the liver.

 

It's possible that compensating effects by other clock-related genes is

keeping the circadian period normal in mice treated with TNF-a, senior author

Adriano Fontana of University Hospital Zurich told The Scientist in an Email.

" This

may explain why TNF-a, which influences the expression of several clock

genes, does not result in a shift of the circadian clock. "

 

Another possibility, however, is that TNF-a is affecting not the central

circadian pacemaker in the SCN, but only peripheral oscillators in the liver or

other tissues, according to Vincent Cassone of Texas A & M University in College

Station, who

wasn't involved in the study. If Period gene expression is suppressed, " you

should get a change in [circadian] period, " he said. Since the authors don't

see that, Cassone suspects that they've found " purely a direct effect on output

and peripheral oscillations, which I think is kind of interesting. "

 

The authors believe that TNF-a is affecting SCN rhythms, because they found a

slight reduction of one of the clock-controlled transcription factors in the

SCN of TNF-a-treated mice. However, they didn't look at expression of the

other clock genes.

 

According to Krueger, the study's findings fit in well with previous findings

about immune response effects on sleep. However, he said, " I don't think

TNF's effects on sleep are entirely dependent on activating or deactivating the

circadian rhythm genes. " TNF-a also controls expression of many other genes,

Krueger said, and some of these likely influence sleep in other ways.

 

From an evolutionary point of view, increased sleep during illness may help

animals to fight off infections or may keep sick animals from socializing and

spreading an infection to others, Fontana said. It's possible that increased

sleep is merely a byproduct of illness, Opp said, but many researchers believe

that " the way we sleep when we are sick facilitates recovery. "

 

 

Melissa Lee Phillips

mail

 

 

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Links within this article

 

K.Y. Kreeger, " Collecting clues to the mammalian clock, " The

Scientist, April 15, 2002.

http://www.the-scientist.com/article/display/12992/

 

G. Cavadini et al., " TNF-a suppresses the expression of clock

genes by interfering with E-box-mediated transcription, " PNAS,

published online July 16, 2007.

http://www.pnas.org

 

J. Lucentini, " The body sleeps, but the genes do not, " The

Scientist, February 16, 2004.

http://www.the-scientist.com/2004/2/16/24/1/

 

Mark Opp

http://www.med.umich.edu/anesresearch/opp.htm

 

S. Akira et al., " Pathogen recognition and innate immunity, " Cell,

February 24, 2006.

http://www.the-scientist.com/pubmed/16497588

 

D.R. Spriggs et al., " Recombinant human tumor necrosis factor

administered as a 24-hour intravenous infusion. A phase I and

pharmacologic study, " Journal of the National Cancer Institute,

September 7, 1988.

http://www.the-scientist.com/pubmed/3411618

 

L.C. Pollard et al., " Fatigue in rheumatoid arthritis reflects pain,

not disease activity, " Rheumatology (Oxford), July 2006.

http://www.the-scientist.com/pubmed/16449363

 

A.N. Vgontzas et al., " Marked decrease in sleepiness in patients

with sleep apnea by etanercept, a tumor necrosis factor-alpha

antagonist, " Journal of Clinical Endocrinology and Metabolism,

September 2004. Sep;89(9):4409-13.

http://www.the-scientist.com/pubmed/15356039

 

J.M. Krueger, J.A. Majde, " Humoral links between sleep and the

immune system: research issues, " Annals of the New York

Academy of Sciences, May 2003.

http://www.the-scientist.com/pubmed/12794042

 

J.P. Roberts, " What sets the biological clock? " The Scientist,

June 10, 2002.

http://www.the-scientist.com/article/display/13096/

 

James Krueger

http://www.vetmed.wsu.edu/research_vcapp/krueger/krueger.asp

 

U. Schibler, P. Sassone-Corsi, " A web of circadian

pacemakers, " Cell, December 27, 2002.

http://www.the-scientist.com/pubmed/2507418

 

N. Cermakian, P. Sassone-Corsi, " Multilevel regulation of the

circadian clock, " Nature Reviews Molecular and Cell Biology,

October 2000.

http://www.the-scientist.com/pubmed/11413490

 

Adriano Fontana

http://www.neuroscience.unizh.ch/e/groups/fontan00.htm

 

Vincent Cassone

http://www.bio.tamu.edu/FACMENU/FACULTY/CassoneV.htm

 

 

 

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