Glucocorticoids In Inflammation Research Articles

Defining the role of glucocorticoids in inflammation.

An established body of knowledge and clinical practice has argued in favor of the use of glucocorticoids in various chronic inflammatory and autoimmune diseases. However, the very well-known adverse effects associated with their treatment hampers continuation of therapy with glucocorticoids. Analyses of the molecular mechanisms underlying the actions of glucocorticoids have led to the discovery of several mediators that add complexity and diversity to the puzzling world of these hormones and anti-inflammatory drugs. Such mediators hold great promise as alternative pharmacologic tools to be used as anti-inflammatory drugs with the same properties as glucocorticoids, but avoiding their metabolic side effects. This review summarizes findings about the molecular targets and mediators of glucocorticoid function.

HDAC2 is required by the physiological concentration of glucocorticoid to inhibit inflammation in cardiac fibroblasts.

We previously suggested that endogenous glucocorticoids (GCs) may inhibit myocardial inflammation induced by lipopolysaccharide (LPS) in vivo. However, the possible cellular and molecular mechanisms were poorly understood. In this study, we investigated the role of physiological concentration of GCs in inflammation induced by LPS in cardiac fibroblasts and explored the possible mechanisms. The results showed that hydrocortisone at the dose of 127 ng/mL (equivalent to endogenous basal level of GCs) inhibited LPS (100 ng/mL)-induced productions of TNF-α and IL-1β in cardiac fibroblasts. Xanthine oxidase/xanthine (XO/X) system impaired the anti-inflammatory action of GCs through downregulating HDAC2 activity and expression. Knockdown of HDAC2 restrained the anti-inflammatory effects of physiological level of hydrocortisone, and blunted the ability of XO/X system to downregulate the inhibitory action of physiological level of hydrocortisone on cytokines. These results suggested that HDAC2 was required by the physiological concentration of GC to inhibit inflammatory response. The dysfunction of HDAC2 induced by oxidative stress might be account for GC resistance and chronic inflammatory disorders during the cardiac diseases.

Endogenous glucocorticoids in inflammation: contributions of systemic and local responses

The anti-inflammatory actions of therapeutic glucocorticoids are well established and these drugs are widely used to treat a variety of inflammatory conditions. It is also clear that endogenously synthesised glucocorticoids have an important role in regulating inflammatory responses. Traditionally, our understanding of the effects of endogenous glucocorticoids has been based on the levels of glucocorticoids within the circulation. These levels are controlled by the hypothalamic-pituitary-adrenal axis. However, more recently it has been established that the local level of glucocorticoids is of potential importance. Situations where the local level of glucocorticoids may differ from the level in the circulation are illustrated in this review. In addition, the mechanisms regulating local glucocorticoid levels and actions are identified. Increasingly, it will be important to understand how the levels of glucocorticoids within the circulation and within the tissues are regulated in a coordinated manner.

Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes.

Eosinophils and neutrophils are closely related, terminally differentiated cells that in vitro undergo constitutive cell death by apoptosis. The onset of apoptosis in both cell types can be delayed by hemopoietins and inflammatory mediators. Although there have been a number of reports demonstrating that glucocorticoids (in particular dexamethasone) antagonize the eosinophil life-prolonging effects of hemopoietins, direct effects of dexamethasone on eosinophil apoptosis have not been documented. In this study we examined the direct effects of glucocorticoids on eosinophil and neutrophil apoptosis in light of their common therapeutic use as anti-inflammatory and anti-allergic/hypereosinophilic agents. We found that treatment with dexamethasone induced eosinophil apoptosis. In contrast, dexamethasone was a potent inhibitor of neutrophil apoptosis. The effect of dexamethasone on both cell types was mediated through the glucocorticoid receptor, i.e., it was abolished by the glucocorticoid receptor antagonist RU38486. This is the first description of an agent that promotes eosinophil apoptosis while inhibiting neutrophil apoptosis, and thus presents a novel approach to the study of control of apoptosis in these closely related cell types as well as increases our understanding of the clinical action of glucocorticoids in inflammation.