THE ANTIBIOTIC RIFAMPICIN IS A NONSTEROIDAL LIGAND AND ACTIVATOR OF THE HUMAN GLUCOCORTICOID RECEPTOR

The glucocorticoid receptor (GR) belongs to a superfamily of ligand-re gulated nuclear steroid hormone receptors. The steps in the signal tra nsduction parkway leading to the biological effects of glucocorticoids (GCs) include sequentially binding of the steroid to the GR ligand bi nding domain (LBD), receptor transformation(1-3), nuclear translocatio n and either positive or negative gene transactivation(4). Rifampicin (RIF) is a macrocyclic antibiotic used as an antituberculosis agent(5) . As the incidence of tuberculosis has been increasing, in part becaus e of the AIDS epidemic, a growing number of patients are being exposed to the adverse effects of this antibiotic(6). Indeed, this compound, as are the GCs (ref. 7), is often implicated in noxious drug interacti ons, because elf its strong ability to induce drug-metabolizing enzyme s(8,9). Moreover, in humans, RIF, as are the GCs (ref. 10), has been d escribed as a potential immunodepressor, associated notably with the r eduction of mitogenic responsiveness of human peripheral blood lymphoc ytes(11,12). Here, we report that RIF activates the human glucocortico id receptor (hGR). Transient expression of wild-type, deleted or mutat ed GRs; sucrose density gradient sedimentation; and the BIAcore techni que strongly suggest that RIF binds to the receptor with the physiolog ical consequence that this antibiotic acts as an immunodepressor. Give n the wide use of RIF in the treatment of coinfection of tuberculosis and HIV, this report is highly relevant to current medical practice.