“In our genome, we have between 1,000 and 2,000 binding sites for hormone-activated glucocorticoid receptors dispersed in the chromatin of our cells,” Dr. Chrousos said. “What’s interesting is that the availability of these binding sites for interacting with the GR-glucocorticoid complex depends on the chromatin landscape, which is tissue- and cell type–specific. This explains, to some extent, why the GR has a certain effect on one tissue and a totally different effect on another.” Thus, even though the signaling system is the same, the landscape of the landing site is not. So the cells recognize these signals differently, resulting in a different glucocorticoid effect.
Intensifying the complexity, Dr. Chrousos and colleagues, as well as other groups, have shown that there are at least 16 GR isoforms, eight of which produce isoforms of the “classic” GR alpha and eight of the GR beta. While GR alpha binds to cortisol, GR beta does not bind glucocorticoids, but is able to heterodimerize with GR alpha, decreasing its effectiveness. Thus, the activity of the alpha receptor is moderated by the beta receptor. GRs, he said, are much more stochastic in their effects than originally thought.
You have to think of the human organism as a collection of different tissues that can respond differently to glucocorticoids, either in a glucocorticoid-hypersensitive or -resistant fashion.
—George P. Chrousos, MD
Pervasive Actions
Dr. Chrousos then summarized other recent discoveries about glucocorticoids’ actions, which include regulation of metabolism and the immune response. For example, a recent study in rats found differences in genomic response to the administration of dexamethasone, depending on the animals’ gender.3 While the majority of the genes responded similarly in the two genders, this sexually dimorphic effect was seen in a significant subset of genes consisting of either stimulation or suppression.
Dr. Chrousos’ team studied the effects of glucocorticoids given to patients with acute respiratory distress syndrome and followed the physiological chain of events resulting in control of inflammation. In those given glucocorticoids, plasma levels of TNF alpha, IL-1, and IL-6 decreased, as did nuclear levels of nuclear factor kappa B (NF-κB), normally high in the cell nucleus of inflamed cells. As such, the GR receptors were able to displace NF-κB from the cell nucleus and inflammation came under control.4
Concordance with Circadian Rhythms
Interestingly, Dr. Chrousos noted, the way in which researchers approach their work has changed over the past 30 years, resulting in new discoveries. As a fellow in the 1980s, he recalled, it was “anathema” to engage in any non-hypothesis-driven research. In those “politically correct” times, he said, such studies were labeled “fishing expeditions.”
