Inflammation, the body's earliest response to damage or infection, can aid the healing process and trigger an immune response against invading pathogens.
But inflammation gone awry can also undermine health, as in diseases such as rheumatoid arthritis or asthma.
Researchers at the University of Illinois have identified a novel pathway that controls the activity of a key protein involved in inflammation. Their findings could have important implications for the treatment of diseases or conditions linked to chronic inflammation.
At the heart of the cell's inflammatory response is a protein complex called NF-kappa B. In the new study, biochemistry professor Lin-Feng Chen and his colleagues deciphered a molecular code that controls its function. Their results appear in the European Molecular Biology Organization (EMBO) Journal .
The NF-kappa B protein complex consists of two subunits that can bind to DNA and regulate the expression of particular genes. The complex acts like a molecular switch that can be turned on when the cell is under attack and then off when the attack has been cleared. Upon activation, it rapidly moves into the nucleus and sets in motion an army of proteins that cause inflammation. Often referred to as the master regulator of the immune system, NF-kappa B belongs to a large family of proteins called transcription factors that control which genes are turned on or off.
"Inflammation is like a chemical storm during which many special chemicals that signal the immune system are released at the site of infection," Chen said.
"NF-kappa B, the protein which is central to the inflammatory response, has to be tightly controlled; otherwise things could go crazy within the body."
Normally, a second protein inactivates NF-kappa B by directly binding to it. But when the cell is under stress (for example, during infection), this inhibitory protein is dismantled. NF-kappa B, now relieved of inhibition, rushes into the nucleus and activates gene expression. Once it finishes its job, NF-kappa B stimulates the production of its inhibitory partner and is itself inhibited again.
Recent studies found that NF-Kappa B also was being degraded in the nucleus, indicating an alternate means by which NF-kappa B activity is regulated in the cell.
"Every step of NF-kappa B activation is tightly controlled," Chen said. He and his colleagues hunted for the signals that could control its degradation and inactivation.
Chen's earlier work gave him important clues about how protein activity can be modified when small chemical groups are added to the protein after it is assembled. This process, called post-translational modification, tags the proteins. Like the sign on the front of a bus declaring its destination, the tags direct proteins to different fates.
"One of the goals of our lab is to study how post-translational modifications affect NF-kappa B activity under normal and diseased conditions," Chen said.