Topic Name: A signaling pathway crucially involved in Crohn's disease and Ulcerative Colitis

Category: Biomedical

Research persons: A. Nenci, C. Becker, M. Neurath, M. Pasparakis

Location: EMBL Monterotondo, Adriano Buzzati-Traverso Campus, Via Ramarini 32, 00016 Monterotondo, Italy

Details

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

About Researchers:

Dr. Arianna Nenci

Postdoctoral Fellow
Rosenthal Group

EMBL Monterotondo, Adriano Buzzati-Traverso Campus, Via Ramarini 32, 00016 Monterotondo, Italy
Tel: +39 06 90091- 271
Fax: +39 06 90091 272
E-mail: arianna.nenci@embl-monterotondo.it

Contact

Visitor address:

L9, 1-2 Room 305
68131 Mannheim, Germany
fon +49 (0) 621/181- 2152
fax +49 (0) 621/181- 2150

christian.becker(at)uni-mannheim.de

Consultation hour: Tuesday 2pm-3pm
contact Ms. Goldner for an appointment

Postal address:

Schloss
68131 Mannheim, Germany

Prof. Dr. med. Markus Neurath

University of Mainz
I. Medizinische Klinik der Univ. Mainz
Langenbeckstrasse 1
55131 Mainz

Tel.: 06131 172374
Fax: 06131 175508
email:neurath@l-med.klinik.uni-mainz.de
 

Dr. Manolis Pasparakis

EMBL Monterotondo, Adriano Buzzati-Traverso Campus, Via Ramarini 32, 00016 Monterotondo, Italy
Tel: +39 06 90091- 222
E-mail: pasparakis@embl-monterotondo.it

Funded:

The European Molecular Biology Laboratory is a non-profit organisation and a basic research institute funded by public research monies from 19 member states. Research at EMBL is conducted by approximately 80 independent groups covering the spectrum of molecular biology. The Laboratory has five units: the main Laboratory in Heidelberg, and Outstations in Hinxton [the European Bioinformatics Institute], Grenoble, Hamburg, and Monterotondo near Rome.

The cornerstones of EMBL's mission are: to perform basic research in molecular biology, to train scientists, students and visitors at all levels, to offer vital services to scientists in the member states, to develop new instruments and methods in the life sciences, and technology transfer.

Molecular Biology Laboratory [EMBL] established the Molecular Medicine Partnership Unit that is staffed by both institutions and co-directed by Andreas Kulozik from Heidelberg University and by Matthias Hentze from EMBL. Andreas and Matthias have successfully worked together on diseases of RNA metabolism for many years, and are dedicated to the success of the MMPU.

The success of their first MMPU group has led to a recent extention of the MMPU, which will further strengthen the link between basic and translationel research in molecular medicine. In the beginning of 2006, the MMPU was joined by the following three new groups:

Matthias Hentze and Andreas Kulozik looking at RNA metabolism in blood diseases

Marcus Mall and Carsten Schultz studying cystic fibrosis

Martina Muckenthaler and Matthias Hentze studying mammalian degenerative diseases due to defects in iron metabolism

Magnus von Knebel-Doeberitz and Peer Bork looking at the identification of cancer markers

The MMPU has an international orientation, with team meetings, an attractive seminar programme, mini-symposia and other teaching activities in English. It is located on the Medical Campus of Heidelberg University, within walking distance from the German Cancer Research Center and the Center for Molecular Biology of Heidelberg University [ZMBH], and a short drive from EMBL. The MMPU is supported by the University of Heidelberg and EMBL. Most research activities are financed by grant support from several research agencies. In the future, the MMPU hopes to receive further support to fertilize its development.