Glucocorticoids in innate immunity: more transactivation than transrepression!

Identification of the mechanism responsible for the beneficial effects produced by glucocorticoids in clinical settings has always been a fascinating task of pharmacology. Novel data produced with human primary monocytes reveals the major mechanism of action: gene reprogramming towards marked transactivation of multiple anti-inflammatory genes.

The seminal observation by Philip Hench et al that adrenal cortex extracts possessed potent antiarthritic properties in humans¹  has produced one of the major breakthroughs in biology and clinical practice. The identification of cortisol, and the ensuing development of several synthetic derivatives, has indeed provided the clinician with strong weapons for treatment of diseases spanning from asthma to arthritis to inflammatory bowel disease. But how do glucocorticoids work? Upon addition to cells, the lipophilic glucocorticoid will rapidly cross plasma membranes to interact with specific cytoplasmic glucocorticoid receptors (GRs). The GR is kept in an inert status by binding to intracellular chaperones (heat shock proteins); however, interaction with the ligand causes dissociation, activation, and dimerization. The homodimer complex (2 glucocorticoid molecules and 2 GR molecules) will travel to the nucleus, where it will bind to specific positive or negative glucocorticoid-response elements²  that are present in the promoter regions of target genes to increase or decrease gene transcription.

In recent years, this model was challenged by the observation that the cytosolic monomeric glucocorticoid-GR complex could bind transcription factors, including nuclear factor-κB (NF-κB) and the complex c-jun/c-fos(activated protein-1 [AP-1]); interference with transcription factor activity could be obtained in several distinct manners,²  but the endpoint would always be blockade of gene expression or transrepression. However, despite the excitement produced in the scientific community, it soon appeared that this molecular mechanism was unlikely to be the sole mode of action for this class of lifesaving drugs, since they retained anti-inflammatory effects in mice deficient for specific subunits of NF-κB.³  In addition, the discovery that glucocorticoids can produce rapid nongenomic effects, which is evident within minutes of addition to platelets or peripheral blood mononuclear cells (PBMCs; see figure),^4,5  suggests a model where glucocorticoids can produce distinct downstream readouts in relation to the type of ligand used, its concentration/dose applied, temporal length of application, and cellular target.

In this issue of Blood, Ehrchen and colleagues demonstrate that the exposure of human monocytes to a low concentration of fluticasone would reprogram the cells toward an anti-inflammatory phenotype. Microarray analysis revealed that more than 100 genes were induced against approximately 40 genes that were being down-regulated; therefore, transactivation does prevail over transrepression. Gene clustering analysis indicated that transactivated genes grouped themselves in the antioxidative, migration/chemotaxis, phagocytosis, and anti-inflammatory/proresolving classes; importantly, changes in gene activity were confirmed with quantitative polymerase chain reaction (PCR) and functional assays.

Another interesting observation made by Ehrchen and colleagues is that glucocorticoids increased monocyte chemokinesis, a response effected via up-regulation of several genes involved in cell mobility; this is likely to be relevant in the context of resolution of inflammation, where monocytes—and other leukocytes—must leave the site of inflammation/infection via the lymphatic system. Another interesting observation was glucocorticoid induction of the formyl-peptide receptor, a G-protein coupled receptor activated by peptides cleaved from the annexin 1 N-terminus⁶  in inflammatory exudates.

In conclusion, the glucocorticoid real mechanism of action has remained “elusive” for many years, and one reason for this is that multiple mechanisms can be operative upon glucocorticoid binding to GRs. Depending on the experimental condition applied, the glucocorticoid may elicit rapid nongenomic effects, transrepressing mechanisms, or, as now reported, delayed transactivating anti-inflammatory/homeostatic responses (see figure). This study by Ehrchen and colleagues challenges transrepression as the major glucocorticoid molecular mechanism, and restores transactivation as the more relevant mechanism, especially when considering that in clinical practice, prolonged treatment with glucocorticoids is often required. It is hoped, as the authors put it, that the current analysis of monocyte reprogramming “… may offer novel targets for future anti-inflammatory strategies.”