The antibiotic rifampicin is a nonsteroidal ligand and activator of the human glucocorticoid receptor

Abstract

The glucocorticoid receptor (GR) belongs to a superfamily of ligand-regulated nuclear steroid hormone receptors. The steps in the signal transduction pathway leading to the biological effects of glucocorticoids (GCs) include sequentially binding of the steroid to the GR ligand binding domain (LBD), receptor transformation, nuclear translocation and either positive or negative gene transactivation. Rifampicin (RIF) is a macrocyclic antibiotic used as an antituberculosis agents. As the incidence of tuberculosis has been increasing, in part because of the AIDS epidemic, a growing number of patients are being exposed to the adverse effects of this antibiotic. Indeed, this compound, as are the GCs, is often implicated in noxious drug interactions, because of its strong ability to induce drug-metabolizing enzymes. Moreover, in humans, RIF, as are the GCs, has been described as a potential immunodepressor, associated notably with the reduction of mitogenic responsiveness of human peripheral blood lymphocytes. Here, we report that RIF activates the human glucocorticoid receptor (hGR). Transient expression of wild-type, deleted or mutated GRs; sucrose density gradient sedimentation; and the BIAcore technique strongly suggest that RIF binds to the receptor with the physiological consequence that this antibiotic acts as an immunodepressor. Given the wide use of RIF in the treatment of coinfection of tuberculosis and HIV, this report is highly relevant to current medical practice.

Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells

“…The mechanism of GR activation in a ligand-independent manner has been the subject of several recent investigations (27,28). In this study, we demonstrate ligand-independent activation of GR by two ␤ 2 -agonists, salmeterol and salbutamol.…”

Horseradish Peroxidase-Catalyzed Oxidation of Rifampicin: Reaction Rate Enhancement by Co-oxidation with Anti-inflammatory Drugs

“…4) It has also been described as an immunosuppressive drug, 5) and it was shown recently that rifampicin and analogues have the potential to block tumour necrosis factor (TNF)-or phorbol myristate acetate (PMA)-induced, nuclear factor kappaB (NF-kB) activation in the Jurkat T-cell line.…”

Alternative treatment of psoriasis - is rifampicin a mild immunosupressor? / Alternativna terapija psorijaze: da li rifampicin ima blago imunosupresivno dejstvo?

“…Rifampicin may also inhibit the secretion of IL-1β and TNF-α (26). Calleja et al demonstrated that rifampicin both binds to, and activates, the human glucocorticoid receptor, which regulates the expression of many genes, including those encoding interleukins that regulate immune responses (27). Most recently, Dubrac et al established that pharmacologic activation of pregnane X receptor (PXR) inhibits T-lymphocyte function (28).…”