Posted on January 28, 2004 at 9:30 a.m.
BIRMINGHAM, AL — A study by researchers at the University of Alabama at Birmingham (UAB) reveals new information about cellular processes involved in the development of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The study, published recently in Nature Immunology, was led by Etty (Tika) Benveniste, Ph.D., chair and professor of the Department of Cell Biology at UAB, with Duane Wesemann, Ph.D., a student in the UAB Medical Scientist Training Program.
“Our findings regarding the activity and function of certain cell proteins were quite unexpected and contrary to what is commonly believed,” Benveniste said. “Although there is still much to learn, they are exciting discoveries because they provide new insight and point to a potential new target of study to further our understanding of autoimmune diseases.”
The investigation centered on the cellular processes initiated by interferon-gamma and tumor necrosis factor (TNF), proteins that regulate the intensity and duration of immune responses. Autoimmune diseases such as rheumatoid arthritis and multiple sclerosis are characterized by elevated levels of these particular proteins.
These proteins work by attaching to receptors on the surface of cells and in turn, signaling the initiation of a series of processes within the cells. “When interferon-gamma attaches to the surface of certain cells called macrophages, signals are initiated that lead to the activation of immune system cells called T-cells, the body’s defenders against disease,” Benveniste said. “However, when macrophages are inappropriately activated, this contributes to disease.”
This process, as well as the signaling process mediated by TNF, have been well explored. “We know that in cells stimulated by interferon-gamma, a protein called STAT responds,” Benveniste said. “In cells stimulated by TNF, a protein called TRADD responds. It is widely believed that TRADD is associated only with TNF signaling. However, we found that TRADD also responds to interferon-gamma signals.”
The TRADD protein has been thought to be present only in the outer region of a cell. However, Benveniste’s research group found that TRADD can travel to the cell’s center, or nucleus. This finding, also contradictory to what cell biologists have long believed, is important because in a cell’s nucleus, a protein’s function may differ significantly.
“Our research shows that in cells missing the TRADD protein, the STAT protein remains activated longer,” Benveniste said. “Although speculative, we believe that once in the nucleus of a cell, TRADD may act to suppress the activity of STAT, in turn regulating the immune response.”
While these findings pose new questions as to how the TRADD protein enters the nucleus and the precise nature of its function, the information learned from the study gives researchers a new understanding of the signaling pathways in immune cells. “At the very least it tells us that in patients with autoimmune diseases, treatments prescribed to block one signaling pathway may not affect just that one pathway and have more profound effects on cellular functions.”