Researchers Identify Molecular Basis Of IBD

[Guest guest]

Source:

European Molecular Biology Laboratory

Date:

March 15, 2007

Researchers

Identify Molecular Basis Of Inflammatory Bowel Disease

Science Daily —

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.

Barb in Texas - Together in the Fight, Whatever it Takes!

Son Ken (32) UC 91 - PSC 99 Listed 7/21 @ Baylor Dallas

[Guest guest]

O.K., now I am really confused! I understood that in ulcerative

colitis there is activation of nuclear factor-kappa B (NF-kB); see

for example:

Andresen L, nsen VL, Perner A, Hansen A, Eugen-Olsen J, Rask-

Madsen J. Activation of nuclear factor kappaB in colonic mucosa from

patients with collagenous and ulcerative colitis. Gut. 2005 Apr;54

(4):503-9. PMID: 15753535.

http://gut.bmj.com/cgi/content/full/54/4/503

In fact medications like sulfasalzine are thought to act by

inhibiting NF-kB activation; see for example:

Gan HT, Chen YQ, Ouyang Q. Sulfasalazine inhibits activation of

nuclear factor-kappaB in patients with ulcerative colitis.

J Gastroenterol Hepatol. 2005 Jul;20(7):1016-24. PMID: 15955209.

" The therapeutic benefits for ulcerative colitis of sulfasalazine

might at least in part be attributed to its ability to inhibit NF-

kappaB activation, resulting in the downregulation of pro-

inflammatory cytokine mRNA expression. "

This is also how steroids are thought to work; see for example:

Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa

B inflammatory bowel disease. Gut. 1998 Apr;42(4):477-84. PMID:

9616307.

http://gut.bmj.com/cgi/content/full/42/4/477

" Corticosteroids strongly inhibit intestinal NF kappa B activation in

IBD in vivo and in vitro by stabilising the cytosolic inhibitor I

kappa B alpha against activation induced degradation. CONCLUSIONS: In

both IBDs, but particularly Crohn's disease, increased activation of

NF kappa B may be involved in the regulation of the inflammatory

response. Inhibition of NF kappa B activation may represent a

mechanism by which steroids exert an anti-inflammatory effect in IBD. "

But this new study (posted by Barb, below) now suggests that

inflammatory bowel disease can actually be CAUSED by blocking NF-kB

activation! Can anyone shed light on this paradox for me? Any insight

would be greatly appreciated.

Best regards,

Dave

>

>

>

> Source:

> <http://www.embl.org> European Molecular Biology Laboratory

>

> Date:

> March 15, 2007

>

>

>

> Researchers Identify Molecular Basis Of Inflammatory Bowel Disease

>

> <http://www.sciencedaily.com> Science Daily - 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.

> Barb in Texas - Together in the Fight, Whatever it Takes!

> Son Ken (32) UC 91 - PSC 99 Listed 7/21 @ Baylor Dallas

>