Thursday, March 15, 2007

Researchers identify defective molecule that triggers inflammatory bowel diseases

[Date: 2007-03-15]

Inflammatory bowel diseases such as Crohn's and Ulcerative Colitis are caused by a vicious cycle of inflammatory signals triggered by a defective signalling molecule, researchers have found.

The work, which was partly funded by the EU's Sixth Framework Programme, is published online by the journal Nature.

Inflammatory bowel diseases such as Crohn's affect more than four million people around the world. Symptoms of Crohn's disease include pain, diarrhoea, tiredness and weight loss. There is currently no cure for this debilitating condition, although it can be managed by steroids and immunosuppressants. Understanding the factors which trigger the inflammation of the bowel is a key focus of research into these diseases.

In this latest piece of research, scientists looked at the role of a signalling molecule called NF-kB, which has been implicated in a range of diseases with inflammatory components such as multiple sclerosis.

Our guts contain large numbers of bacteria which help us to digest our food. However, if they penetrate the wall of the intestine, they can cause diseases. To stop this happening, our intestines are lined with a layer of cells called an epithelium which acts as a barrier, keeping the bacteria where they belong inside the intestine.

To investigate the role of NF-kB in all this, the researchers created mice whose intestinal epithelial cells did not produce a protein called NEMO, which activates NF-kB. The mice went on to develop severe intestinal inflammation, similar to colitis in humans, and closer inspection revealed that their gut linings had been damaged, allowing bacteria into the walls of the intestine and triggering a vicious cycle of inflammatory signals which cause the symptoms of the disease.

'NF-kB acts as a survival signal for cells,' explained Manolis Pasparakis of the University of Cologne. '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.'

When bacteria break through the gut epithelium into the intestinal wall, they trigger a strong immune response from the intestinal immune system. Some of the signals sent out by the immune system bring about the symptoms of inflammation.

'This is where the vicious cycle closes,' commented Markus Neurath of 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.'

As the immune systems of mice and humans are similar, the researchers hope their work will lead to the development of new treatments for these painful diseases.

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Category: Projects
Data Source Provider: European Molecular Biology Laboratory (EMBL) and Nature
Document Reference: Nenci, A. et al. (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature, published online 14 March 2007.
Subject Index: Coordination, Cooperation; Medicine, Health; Scientific Research

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