| First Author | Van Bogaert T | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 30 | Pages | 26555-67 |
| PubMed ID | 21646349 | Mgi Jnum | J:175378 |
| Mgi Id | MGI:5285462 | Doi | 10.1074/jbc.M110.212365 |
| Citation | Van Bogaert T, et al. (2011) Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock. J Biol Chem 286(30):26555-67 |
| abstractText | 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 TNFalpha, a strong pro-inflammatory mediator in numerous inflammatory diseases, compromises the protective function of the glucocorticoid receptor (GR) against TNFalpha-induced lethal inflammation. Indeed, protection of mice by dexamethasone against TNFalpha lethality was completely abolished when it was administered after TNFalpha stimulation, indicating compromised GR function upon TNFalpha challenge. TNFalpha-induced GCR was further demonstrated by impaired GR-dependent gene expression in the liver. Furthermore, TNFalpha down-regulates the levels of both GR mRNA and protein. However, this down-regulation seems to occur independently of GC production, as TNFalpha 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 TNFalpha-induced shock, as supported by our studies with GR heterozygous mice. We propose that by inducing GCR, TNFalpha 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 TNFalpha is intimately involved. |
