BioWorld International Correspondent

LONDON - A signaling pathway that holds the reins on many different inflammatory responses appears to play a vital role in the development of inflammatory bowel disease in mice.

The mechanism, identified by researchers working in Germany, which also may underlie inflammatory bowel disease in humans, provides a new paradigm for understanding how the disease develops. Genetically modified mice used for the study will, the researchers said, make a good model for testing new therapies for the condition.

The signaling pathway they have identified as crucial in inflammatory bowel disease is that controlled by the transcription factor NF-kappa B. Activation of that molecule leads to production of a range of inflammatory molecules, such as tumor necrosis factor (TNF), and activation of cells of the immune system.

Previous studies have identified inhibitors of NF-kappa B as potential treatments for inflammatory bowel disease. The latest discovery, however, proves that - in the epithelial cells of the colon - NF-kappa B plays a protective role.

Manolis Pasparakis, professor of genetics at the University of Cologne in Germany, told BioWorld International: "There are already some small-scale trials being done with NF-kappa B inhibitors as therapy for inflammatory bowel disease. But our data will raise a flag over this approach, because if levels of inhibition in epithelial cells reach a significant level, there is a risk of either causing the disease or making it worse."

Pasparakis and his colleagues describe their work in a paper in the March 14 issue of Nature titled: "Epithelial NEMO links innate immunity to chronic intestinal inflammation."

Before their study, many experiments in both humans and animal models had suggested that activation of NF-kappa B in the gut played a role in the development of the disease. There also was some evidence that the epithelium of the gut was important in helping the immune system to patrol the gut - keeping potentially harmful bacteria in the gut lumen and not allowing these to penetrate the gut wall.

Pasparakis said: "The gut has many different cell types - immune cells, endothelial cells and epithelial cells, for example - so it is very difficult to talk about the role of NF-kappa B in general. We therefore decided to study the role of NF-kappa B solely in the epithelial cells of the gut."

Using conditional knock-out techniques, the researchers developed mice that specifically lacked expression of certain genes in their intestinal epithelial cells. The genes the animals lacked encoded either a protein called NEMO, or molecules called IKKalpha or IKKbeta. All are essential for activation of NF-kappa B.

The effect on the mice was very clear, Pasparakis said. "They did not seem well, they had diarrhea and some blood was present in their stools. When we carried out a miniature version of endoscopy on these animals, we could see that they had severe colitis. Histological studies, and gene expression analysis, also showed evidence of severe inflammation, with infiltration of immune cells, inside the tissue of the colon," he said.

Their observations convinced team members that they were dealing with a new and important disease model for inflammatory bowel disease.

Further experiments showed that, in those animals, the epithelial lining of the gut began to lose its integrity. Here and there, groups of epithelial cells had died, allowing bacteria to penetrate through the gut mucosa. There, the bacteria encountered the immune cells of the gut, which mounted a strong immune response, secreting signals that cause the release of inflammatory molecules, including TNF.

"TNF has a very serious side effect on cells that cannot activate NF-kappa B," explained Pasparakis. "It kills them."

The result is a vicious circle, where the release of TNF kills more epithelial cells, which opens up more gaps in the epithelium, allowing in more bacteria, which causes more inflammation, and so on. "In this situation, it is impossible for the epithelium to heal itself," said Pasparakis.

"We hope one day to be able to develop new treatments for this disease, using the information we have learned," Pasparakis said. "But our immediate priority is to understand in greater detail the mechanisms that cause the disease."

Future studies will focus on finding out if all bacteria can cause the disease, or only certain species. The team plans to use "germ-free" mice, which lack bacteria in their intestines, to confirm that they will not develop the disease even though they lack NF-kappa B in their intestinal epithelial cells. The researchers also want to find out what effect probiotic bacteria might have on the pathology of the disease.

Studies to discover if some humans with inflammatory bowel disease have mutations in the genes encoding the proteins that are needed for NF-kappa B activation are under way.