Scientists have identified a key component of steroids’ effects on the immune system, a possible first step toward developing new drugs that can offer the same benefits as steroids without the many potentially serious side effects.
Louis J. Muglia, M.D., Ph.D., associate professor of molecular biology and pharmacology and of pediatrics, led a research team that published the new insight in the October issue of Nature Medicine.
Louis J. Muglia
By activating immune system cells known as T-cells, Muglia’s team linked steroids to the suppression of an inflammatory compound known as cyclooxygenase-2 (COX-2). The compound acts as a kind of immunological lighter fluid, speeding and expanding a number of inflammatory processes designed to destroy harmful invaders.
When this immunological firestarting is misdirected at the body’s own tissues, autoimmune and inflammatory diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease can result.
Doctors have used steroids for decades to control such diseases, but not without costs. Side effects of high doses can include bone loss, obesity, diabetes, growth impairment and mood alterations.
“For many of these diseases, there’s no alternative to steroids,” Muglia said. “It’s very clear, though, that we’re really limited in how high a dosage we can give patients and how long we can treat them because of the side effects.”
Judson Brewer, first author on the paper and a student in the Medical Scientist Training Program at Washington University, expressed amazement at how little is known of steroids’ effects at the molecular level and how much progress he and his colleagues were able to make in the study.
In the top panel, flourescently labeled glucocorticoid receptors are distributed throughout the cell. After the addition of steroids (bottom panel), the fluorescent glucocorticoid receptors become localized entirely to the cell’s nucleus, where they regulate inflammatory genes.
“The goal here was just to go out and further science and maybe — if we were really lucky — do something that would help people,” Brewer said. “It looks like we might be moving toward that second goal a lot faster than I thought.”
To zero in on how steroids work, Muglia studied their effects on the glucocorticoid receptor, a protein found within cells throughout the body. Natural steroids made by the adrenal glands normally bind to these receptors.
Scientists knew those binding interactions were important for human survival and prevented potentially deadly consequences.
“Prior to the development of artificial steroids in the 1950s, people diagnosed with adrenal insufficiency, which left them with low levels of these natural steroids, only survived about a year,” Muglia said.
In this study, funded by the National Institutes of Health and Pfizer, researchers in Muglia’s lab genetically disabled the glucocorticoid receptor protein in T-cells in mice. They then gave the mice injections of antibodies and other compounds that attack T-cells.
Activated by the attack, the T-cells mounted a counterattack. In experimental mice, the counterattacks spiraled quickly and fatally out of control.
When scientists looked for the genes that were out of control in the T-cells, they found unusually high levels of COX-2, a protein linked to rheumatoid arthritis, infections and other difficulties.
To see if this compound was connected to the experimental mice’s fatal reactions, researchers treated a new batch of experimental mice with drugs to suppress COX-2 and repeated the attack on T-cells. Many more mice survived.
“This suggests that it may be very useful to look at treating patients with adrenal insufficiency or resistance to steroid treatment with COX-2 inhibitors,” Muglia said.
Muglia’s group is working to check its theory of steroid action in mouse models of autoimmune diseases such as lupus and multiple sclerosis. Muglia and Brewer have applied for a patent on the potential new use for COX-2 inhibitors.