For good reasons, glucocorticoids (GLs) have been the cornerstone of immunosuppressive therapy in humans and animals. Their impact on immunomodulation reflects inhibition at every stage of the immune response, including both innate and acquired, and cell- mediated responses; the humoral response, however, is minimally directly affected.

Molecular Mechanism of Action : The effects of GLs are generally recognized to be dose dependent. GLs bind to receptors that are complexed with heat shock proteins in the cytoplasm of the target cell (Hsp 70 and 90). Binding causes the receptor to dissociate from the heat shock protein; the GL and receptor then move into the nucleus where the GL binds to specific DNA sequences or receptors called GL responsive elements (GRE). Once activated, the activated ligand-receptor influences gene expression by binding to GRE in the promoter regions of GL-regulated genes (positive GRE), or by repressing genes through negative GRE (nGRE). The GL receptor (GR) generally has a lower affinity for nGRE compared to pGRE. Two types of interaction occur between the GL and either GRE: cis or trans, and for each, either activation or repression. Cis actions involve binding to specific DNA recognition (direct transcription) sites whereas trans actions involve protein-protein coupling that modulates other transcription factors (eg, NFk-B, AP-1, STAT-5or NF-AT) such that their activity is modulated (indirect, or transactivation). The largely undesirable metabolic effects associated with long-term GLC therapy appear to be mediated by activation (particularly cis?), whereas desirable anti-inflammatory and immunomodulatory effects appear to reflect repression (eg, particularly trans?, et nGREs). Trans nGRE interface also appear to occur at lower concentrations compared to cis effects, thus offering a mechanism of minimizing side effects by using lower doses. Alternative pathways increasing can be expected to be specifically targeted by "designer or dissociative GLC" that are more potent for trans repression rather than other actions. Dexamethasone and prednisolone are examples of a "symmetrical" GLC, characterized by equal binding affinity for both cis and trans actions (or trans repression and activation). In contrast, medroxyprogesterone acetate is predominately transrepressive.

Glucocorticoid Resistance : Human patients may fail to respond to GLs. Causes include poor compliance and poor bioavailability as well as GL resistance (both familial and iatrogenic). Resistance may reflect decreased receptor number (eg, down regulation) or affinity. Reversible down-regulation isa documented sequela of GL treatment (demonstrated in T-lymphocytes of humans receiving GL to treat host-versus graft rejection). This type of resistance might be avoided by higher doses of GL, including pulse dosing. A relative imbalance of GL receptor isoforms may also be responsible: the α isoform binds to GLs, DNA and transcription factors, thus modulating transcription, whereas the β isoform binds to DNA, but not other ligands and fails to activate transcription, thus potentially interfering α isoform actions. Some human patients with severe IBD that fail to respond to high doses of GLs have poor antiproliferative response by blood T-lymphocytes whereas responder completely inhibit. A similar situation has been demonstrated for other chronic allergy-based diseases, such as asthma or rheumatoid arthritis, and renal allograft rejection. Other factors that may contribute to poor response to GLC include overexpression of the multidrug resistance gene (MDR1 polymorphism)which might be reversible by co administration of cyclosporine, an inhibitor of P-glycoprotein.