Glucocorticoids and Inflammation Revisited: The State of the Art

Abstract

Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock protein-bound glucocorticoid receptors that translocate into the nucleus, where they regulate the transcriptional activity of responsive genes by binding to specific promoter DNA sequences (transactivation) or by interacting with transcription factors (transrepression). By interacting with different signaling pathways, newly characterized nuclear receptor coregulators enhance or diminish the actions of glucocorticoids, thus explaining the gene-, cell-, tissue- and context-dependent actions of glucocorticoids. Glucocorticoids modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular [T helper (Th)1-directed] immunity and promote humoral (Th2-directed) immunity and tolerance. The past decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance of inflammatory, autoimmune and allergic diseases. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in the glucocorticoid sensitivity, dependency and resistance of these diseases. Although glucocorticoids increase susceptibility to opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, such as that observed in septic shock and acute respiratory distress syndrome, when administered in a sustained fashion throughout the course of the disease. Glucocorticoids produce their cardiovascular, metabolic and antigrowth side effects through molecular mechanisms distinct from those involved in immunomodulation. Fortunately, the first generation of tissue- and immune- versus cardiovascular/metabolic effect-selective glucocorticoids is available for study and further improvement. ‘Designer’ glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases.

Long-Term Alterations in Neuroimmune Responses after Neonatal Exposure to Lipopolysaccharide

“…Thus, a more proximal target in the cascade of cellular events would seem a more likely site of action. Glucocorticoids also block transcription of the mRNA of proinflammatory cytokines (Barber et al, 1993;Chai et al, 1996;Tatro, 2000;Franchimont et al, 2003), making it possible that there is an alteration in the profile of proand anti-inflammatory cytokines that is generated in adults after LPS. For example, either a reduction in IL-1␤ and IL-6 or an increase in such anti-inflammatory cytokines as IL-10 (Cartmell et al, 2003) and IL-1ra (Cartmell et al, 2001) could alter the ability of LPS to activate the endothelial cells where the COX-2 is generated.…”

Is 11β-hydroxysteroid dehydrogenase type 1 a good therapeutic target for blockade of glucocorticoid actions?

“…Glucocorticoids are ubiquitous, highly pervasive nuclear hormones (3,4). They exert their actions in almost all tissues, influencing the expression of a large proportion of the human genome.…”

“…Binding of the glucocorticoid to its receptor is followed by a multistep process, ultimately changing the transcription rates of target genes. A large number of molecules participate directly or indirectly in the glucocorticoid signaling cascade (3,5). Glucocorticoids are pivotal in many aspects of resting and stress-related homeostasis, the latter including both behavioral and physical adaptation (3,6).…”

“…A large number of molecules participate directly or indirectly in the glucocorticoid signaling cascade (3,5). Glucocorticoids are pivotal in many aspects of resting and stress-related homeostasis, the latter including both behavioral and physical adaptation (3,6). Resting homeostasis depends on the presence of a constant day-to-day exposure of our tissues to glucocorticoids, while the secretion of these hormones is increased during stress for a limited time period.…”

Targeted Delivery of Surface Modified Nanoparticles: Modulation of Inflammation for Acute Lung Injury

“…Furthermore, they downregulate the expression of chemokines and adhesion molecules on these cells. 72,[81][82][83] Studies in vitro demonstrate a direct effect of GCs on cultured ECs and isolated neutrophils to inhibit expression of adhesion molecules. [84][85][86] Several case series reports 87,88 suggested that glucocorticoids could lower mortality in some patients with severe ALI when administered several days after ALI onset.…”