A scientific team reports that high levels of the oncogenic Bcl-3 protein lead to chronic intestinal diseases. Their study (“Elevated Levels of Bcl-3 Inhibits Treg Development and Function Resulting in Spontaneous Colitis”) appears in Nature Communications.
Chronic intestinal disorders, such as ulcerative colitis and Crohn's disease, are caused by the body's own immune defense system. Sufferers frequently experience episodic symptoms such as abdominal pain, cramps, and diarrhea. Researchers are still trying to identify the precise underlying origins of these problems. A group led by Nadine Hövelmeyer, Dr. rer. nat., and Ari Waisman, Ph.D., of the Mainz University Medical Center, in collaboration with Elke Glasmacher, Ph.D., of Helmholtz Zentrum München has discovered a new mechanism that causes intestinal inflammation.
“With the help of our cooperation partners, we were able to demonstrate that the level of the Bcl-3 protein, which also plays a role in the development of various cancerous diseases, is elevated in the intestinal tract of colitis patients and is indeed a trigger of the disease,” said Dr. Hövelmeyer, head of the work group at the Mainz-based Institute for Molecular Medicine. According to the study, Bcl-3 impacts intestinal health through interaction with the regulatory T cells (Tregs) whose main task is to prevent overreaction of the immune system.
“We were able to demonstrate that Bcl-3 suppresses the activation of Tregs by preventing the necessary genes from being read,” explained Dr. Glasmacher, head of the team at the Institute for Diabetes and Obesity in Munich. “Bcl-3 interacts with the transcription factor p50, which is otherwise responsible for activation, and blocks it.”
“Consequentially, the regulatory T cells remain passive, the immune system is no longer regulated, and inflammatory processes begin to take place. Experiments using various models have revealed that elevated quantities of Bcl-3 cause certain cells to migrate to the intestines, where they trigger a severe inflammatory response,” Sonja Reissig, Ph.D., lead author of the paper and research associate at Mainz University Medical Center, pointed out.
“The results represent a major contribution toward our understanding of chronic intestinal inflammation and hopefully over the long term will help us discover aspects that we can target with new therapies,” concluded Dr. Hövelmeyer.
The team is currently focusing on the search for new active agents that will prevent the interaction between Bcl-3 and p50, thus maintaining normal Treg functionality.