Gene-specific mechanisms direct glucocorticoid-receptor-driven repression of inflammatory response genes in macrophages

Inflammation is one of the body’s responses to fight infection and heal tissue damage. The response is controlled by hundreds of genes, which fall into two classes. In the first class, an injury or infection triggers the enzyme RNA Polymerase to bind to and transcribe the gene into long RNA strands, which are then translated into the proteins that play a role in the inflammation response. The second class has a more quick-fire response. RNA Polymerase binds to these genes even without an injury or infection to serve as a trigger. But most of the time the enzyme only transcribes the beginning of these genes. This is because it is inhibited by a so-called negative elongation factor, which acts like a brake. For this second class of genes, an infection or injury triggers the release of the negative elongation factor from the enzyme, and allows RNA Polymerase to transcribe the full RNA strand. In excess, inflammation can be dangerous. The body’s way of limiting or controlling inflammation is via steroid hormones called glucocorticoids. These bind to the glucocorticoid receptor, which acts to switch off the inflammatory genes. But exactly how the receptor does this has not been fully understood. Sacta et al. investigated how the glucocorticoid receptor turns off these gene complexes. Experiments looking at white blood cells in mice found that the receptor can switch off both groups of inflammatory genes, but by a different mechanism for each class. Sacta et al. discovered that in the first gene class, the receptor blocks proteins that open up the DNA for RNA Polymerase, so it could not bind to the gene. In the second class, the receptor stops the release of the brake-like negative elongation factor from RNA Polymerase. As a result, the enzyme stalls at the beginning of the gene and fails to make a full-length transcript required to make the necessary protein. Glucocorticoids are often used as drugs to treat chronic inflammation, but they can have debilitating side effects. Understanding how the glucocorticoid receptor switches off inflammatory genes could help to design drugs with fewer side effects to treat chronic inflammation, and diseases caused by specific inflammatory genes.