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| Cologne/Mainz/Monterotondo, 14 March 2007 |
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| Researchers identify molecular basis of inflammatory
bowel disease
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Scientists decipher a signaling pathway crucially involved in Crohn's
disease and Ulcerative Colitis
Deutsch
Italiano
Press
Release 14 March 2007 [PDF]
Inflammatory
bowel diseases, such as Crohn's disease and Ulcerative Colitis,
severely impair the lives of more than four million people worldwide.
The development of effective therapies against these diseases
requires an understanding of their underlying molecular mechanisms.
Researchers from the Universities of Cologne and Mainz in
Germany, the Mouse Biology Unit of the European Molecular
Biology Laboratory [EMBL] in Italy and their collaborators, have
now deciphered a molecular signal that triggers chronic intestinal
inflammation. The study, which is published in the current
online issue of Nature, shows that blocking a signaling molecule
causes severe intestinal inflammation in mice and reveals a
molecular mechanism that is likely to also underpin human
inflammatory bowel disease.
Our gut is home to an enormous number of bacteria, which live
in harmony with us and help in food digestion. If they penetrate
the wall of the intestine, however, these bacteria can become
harmful and cause diseases. This is why a thin, continuous layer
of interconnected cells, called an epithelium, lines the intestinal
surface creating a barrier that prevents bacteria from crossing that
border. The mechanisms that control the integrity of the epithelium
and contribute to maintaining a healthy gut have remained
unknown.
Arianna Nenci from the group of Manolis Pasparakis at the
University of Cologne and Christoph Becker, a member of
Markus Neurath's group in Mainz, investigated the role of NF-κB,
a signaling molecule that helps cells cope with stress, in the intestinal
epithelium. Using sophisticated genetic methods, they generated
a mouse model that does not express NEMO, a protein
needed to activate NF-κB, in intestinal epithelial cells. As a result,
these mice developed severe chronic intestinal inflammation very
similar to Colitis in humans.
"A close look at the mice revealed that their gut epithelium was
damaged," says Manolis Pasparakis, who recently moved from
heading a lab at EMBL to becoming a professor at the University
of Cologne. "NF-κB acts as a survival signal for cells. Without the
molecule cells are much more likely to die and this is what happened
in the intestines of our mice; individual epithelial cells died
disrupting the gut lining."
Through these gaps bacteria could penetrate the intestinal wall.
Right behind the gut epithelium lie cells of the intestinal immune
system, the biggest immune system of our body. It detects the
invading bacteria and generates a strong immune response to
fight off the invaders. In the process of combating the bacteria, the
immune cells secrete a cocktail of signals that bring about the
symptoms of inflammation.
"This is where the vicious cycle closes," explains Markus Neurath,
professor at the University of Mainz. "Inflammatory signals also
reach the epithelial cells that due to the lack of NF-κB are very
sensitive to them and die. The death of more epithelial cells creates
bigger gaps in the gut lining so that more bacteria enter. The
result is a constant immune response leading to chronic inflammation
as we know it from inflammatory bowel diseases in
humans."
The finding that defective NF-κB signaling in the gut epithelium
initiates the outbreak of inflammation in the intestine provides a
new paradigm for the pathogenesis of inflammatory bowel disease.
Since the immune systems of mice and humans are very similar,
the insights gained through the mouse model are steps
towards a better understanding of the mechanisms causing
human inflammatory bowel diseases and may pave the way for
novel therapeutic approaches.
Source Article
A. Nenci, C. Becker, M. Neurath, M. Pasparakis et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation,
Nature, 14 March 2007
Press Contacts
Anna-Lynn Wegener
Press Officer
EMBL Heidelberg
Tel: +49 6221 387-8452
Email: wegener@embl.de |
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