Abstract
As glucocorticoid resistance (GCR) and the concomitant burden pose a worldwide problem, there is an urgent need for a more effective glucocorticoid therapy, for which insights into the molecular mechanisms of GCR are essential. In this study, we addressed the hypothesis that TNFα, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNFα-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNFα lethality was completely abolished when it was administered after TNFα stimulation, indicating compromised GR function upon TNFα challenge. TNFα-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNFα down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNFα also resulted in down-regulation of GR levels in adrenalectomized mice. These findings suggest that the decreased amount of GR determines the GR response and outcome of TNFα-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNFα inhibits a major brake on inflammation and thereby amplifies the pro-inflammatory response. Our findings might prove helpful in understanding GCR in inflammatory diseases in which TNFα is intimately involved.
Highlights
Tumor necrosis factor alpha (TNF␣) is a strong pleiotropic pro-inflammatory cytokine
We show that high doses of TNF␣ cause glucocorticoid resistance (GCR) in the liver: (i) when dexamethasone was administered after TNF␣ injection, it did not protect against a lethal dose of TNF␣; (ii) a high dose of TNF␣ impaired the transactivation and transrepression actions of glucocorticoid receptor (GR)
To further examine whether TNF␣ blocks GR function, we investigated in TNF␣-treated mice the hepatic expression of a typical GR-transactivated gene (Tsc22d3, which encodes GILZ) and a typical GR-transrepressed gene, il1
Summary
We addressed the hypothesis that TNF␣, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNF␣-induced lethal inflammation. Several of these pathologies are currently treated with TNF␣ inhibitors (5, 6) These anti-TNF␣ molecules are very expensive, they cause many side effects, e.g. increased sensitivity to bacterial infections (7), and many patients are resistant to this treatment. Another effective treatment of inflammatory diseases is administration of synthetic glucocorticoids (GCs), such as dexamethasone. Glucocorticoids have impressive anti-inflammatory effects and are frequently used to treat a wide variety of inflammatory and autoimmune diseases This treatment is based on the knowledge of the role of natural GCs as an endogenous brake on inflammation. Further elucidation of the mechanism of TNF␣-induced GCR could lead to the development of better therapeutic strategies for GC-insensitive patients suffering from TNF␣-mediated diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
