Several nuclear receptor proteins appear to overlap in their ability to exert anti-inflammatory effects, according to new research by scientists at the University of California, San Diego (UCSD).
Nuclear receptors are important drug targets for a number of diseases, for example, glucocorticoid receptors for asthma and arthritis. But use of drugs targeting these receptors is sometimes limited by unwelcome side effects. The new findings may suggest a way to overcome this obstacle.
In a paper being published in the September 9 issue of the journal Cell, Christopher Glass, M.D., Ph.D., professor of cellular and molecular medicine at the UCSD School of Medicine, and his colleagues show that three nuclear receptor proteins - glucocorticoid, PPAR gamma and LXR - can work together to repress the cellular responses to certain kinds of pro-inflammatory molecular signaling. These nuclear receptors are important in "turning off" inflammatory responses to bacteria or viruses and allowing the cells to return to a normal state.
"Basically, we are looking at a 'tuning system' to maintain a proper level of immunity, but without an inappropriate inflammatory response that would contribute to a chronic disease state," Glass said.
The researchers have also, for the first time, identified on a genome-wide level how these proteins work to influence the body's inflammatory response. By identifying the molecular mechanism by which each receptor inhibits particular genes involved in anti-viral responses, more powerful drugs could be developed to fight immune diseases such as arteriosclerosis and arthritis, with fewer side effects.
"We now have a molecular understanding of why inflammatory responses caused by certain infections are sensitive to glucocorticoid drugs for example, while others are resistant," said Glass. "These observations further explain how drugs used to inhibit one type of inflammation could basically cripple the immune system to respond to specific viral infections and make that disease much worse."
Glass's studies of nuclear receptors have focused on their regulation of gene expression in the macrophage, a basic cell that recognizes structures or patterns on pathogens that aren't present in normal cells. The macrophage is responsible for producing and responding to hormone-like molecules that control inflammation - important for the understanding of immune diseases such as arteriosclerosis, psoriasis and rheumatoid arthritis that are triggered by autoimmune responses. While macrophages and other immune cells are essential against infectious organisms, they can also promote chronic inflammatory diseases.