Molecular mechanisms of glucocorticoid action: what is important?

Inflammatory diseases such as asthma and rheumatoid arthritis are characterised at the molecular level by chronically increased expression of multiple cytokines, chemokines, kinins and their receptors, adhesion molecules, and inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and the inducible cyclooxygenase (COX-2).1 At the cellular level, inflamed regions show a substantial influx of various inflammatory cells, arterial dilation, increased blood flow, plasma protein leakage, and oedema whilst, in the case of chronic asthma, substantial remodelling of the airways is observed involving excessive smooth muscle proliferation. However, these parameters of inflammation are effectively reduced by treatment with glucocorticoids by both direct and indirect mechanisms.2 3 For example, the reduced eosinophilia following glucocorticoid treatment in asthmatic subjects arises by direct promotion of eosinophil apoptosis and indirectly by suppressing receptor expression and production of cytokines or growth factors.4 These include factors such as interleukin (IL)-3, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF), and eotaxin which are involved in eosinophil maturation, recruitment, and survival. Similarly, glucocorticoids reduce T cell proliferation and increase T cell apoptosis via mechanisms that are at least partly the result of inhibition of the T cell growth factor, IL-2.5-8 Likewise, monocyte apoptosis is increased and influx of other infiltrating inflammatory cells is also repressed.2 9 Again, this is partly caused by reduced expression of adhesion molecules, both on migrating and target cells, as well as reduced expression of cytokines and chemokines from sites of inflammation. Therapeutically, the ability to suppress a number of inflammatory indices makes glucocorticoids among the most potent anti-inflammatory agents currently available for the treatment of chronic inflammatory diseases such as asthma.2 3 The clinical efficacy of synthetic glucocorticoids such as prednisolone or dexamethasone stems from their ability to mimic natural glucocorticosteroids. Bodily insults, including inflammation, pain, infection or even mental …