Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Feedback loop explains inflammatory effect on intestinal lining

19.03.2010
Signals released by immune cells during a bout of inflammatory bowel disease interfere with intestinal cells' ability to regenerate. Yet people with inflammatory bowel diseases have a significantly higher risk of developing colon cancer: a hyper-activation of growth in those same intestinal cells.

Researchers at Emory University School of Medicine have identified a feedback loop involving a growth-regulating circuit in intestinal cells, which helps explain these apparently contradictory observations. The findings also suggest that interfering with one component of the feedback loop—a protein called "dickkopf 1" —may aid in controlling inflammatory bowel diseases.

The results are published online and scheduled for publication in the March 26, 2010 issue of the journal Immunity.

Senior author of the paper was Asma Nusrat, MD, Emory professor of pathology and laboratory medicine. The research was conducted by postdoctoral fellows Porfirio Nava, Stefan Koch and Mike Laukoetter. Laukoetter is now at the University of Münster in Germany.

The cells lining the intestine, or intestinal epithelial cells, are normally able to repair breaks in the lining by dividing and migrating until the wound has been healed, Nusrat explains. In inflammatory bowel diseases such as Crohn's or ulcerative colitis, immune cells release signals that prevent this repair and cause epithelial cells to die.

Nusrat and her colleagues examined mice treated with a chemical, dextran sulfate, which gives them colitis. The most prominent signaling molecules given off by immune cells in inflamed intestinal tissue were the cytokines ("cell movers") interferon-gamma and tumor necrosis factor-alpha. When the researchers treated intestinal cells by themselves in dishes with these cytokines, the cells had a burst of growth but then started to die out after three days.

"We were puzzled when we saw that cytokines induced activation of a pathway that should lead to cell division and cell survival, not cell death. It was not immediately clear to us why the epithelial cells were dying after exposure to cytokines despite stimulation of this survival pathway," Nusrat says.

A set of proteins together making up a regulatory circuit, collectively known as the Wnt pathway, controls the growth of intestinal epithelial cells. Most colon cancer cells have mutations in their DNA that push this circuit into overdrive. However, the circuit has to work at a moderate level or intestinal cells will not grow.

Nusrat's team found that prolonged exposure to the cytokines induces intestinal cells to give off a protein called dickkopf, which quenches the Wnt pathway and eventually kills the cells.

In mice with a bout of colitis, activity by the intestinal epithelial cells comes in two phases: mild growth for a few days, followed by cells dying out and then growth in areas next to ulcers in the intestinal lining, the authors found.

"Some areas of the intestinal epithelium are able to overcome inhibition of the Wnt pathway, perhaps by inactivating dickkopf," Nusrat says. "Our studies suggest that hyper-stimulation by inflammatory cytokines may be one of the mechanisms making patients with inflammatory bowel diseases significantly more susceptible to cancer development."

The authors speculate that the experimental chemotherapy drug triciribine, which could prevent cells from making dickkopf, could be useful in controlling specific stages of active inflammation in colitis. Another potential tool for controlling inflammation can be antibodies to dickkopf, they say.

The research was supported by the National Institutes of Health, the Crohn's and Colitis Foundation of America and the German Research Foundation.

Reference: P. Nava et al. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity (2010)

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has $2.3 billion in operating expenses, 18,000 employees, 2,500 full-time and 1,500 affiliated faculty, 4,500 students and trainees, and a $5.7 billion economic impact on metro Atlanta.

Learn more about Emory's health sciences: http://emoryhealthblog.com - @emoryhealthsci (Twitter) - http://emoryhealthsciences.org

Holly Korschun | EurekAlert!
Further information:
http://www.emory.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>