Molecular Basis Of Inflammatory Bowel Disease Identified By Researchers

[Guest guest]

Molecular Basis Of Inflammatory Bowel Disease Identified By

Researchers

17 Mar 2007

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-kB, 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-kB, 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-

kB 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-kB 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-kB 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.

###

Contact: -Lynn Wegener

European Molecular Biology Laboratory

http://www.medicalnewstoday.com