2015
DOI: 10.1038/ncomms8796
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Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1

Abstract: Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by gluc… Show more

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Cited by 136 publications
(126 citation statements)
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“…The B6.Cg-Tg(TcraTcrb)425Cbn/j (OTII) mice were obtained from Fundación Instituto Leloir. The GR CD11cCre (Nr3c1 tm2Gsc Tg(Itgax-cre)1-1Reiz) and GR flox (Nr3c1 tm2Gsc ) mice were obtained as previously described3963. Studies were approved by the Institutional Care and Use Committee (CICUAL #0001) FCEyN, University of Buenos Aires.…”
Section: Methodsmentioning
confidence: 99%
“…The B6.Cg-Tg(TcraTcrb)425Cbn/j (OTII) mice were obtained from Fundación Instituto Leloir. The GR CD11cCre (Nr3c1 tm2Gsc Tg(Itgax-cre)1-1Reiz) and GR flox (Nr3c1 tm2Gsc ) mice were obtained as previously described3963. Studies were approved by the Institutional Care and Use Committee (CICUAL #0001) FCEyN, University of Buenos Aires.…”
Section: Methodsmentioning
confidence: 99%
“…However, these prior studies did not specifically recognize cooperative regulation of anti-inflammatory targets by GR and p65 as a potential mechanism underlying the therapeutic effect of GCs. Instead, several studies, including our own publication on regulation of TNFAIP3 by GR and p65 and subsequent work by other groups on Sphk1 and IRAK3 (37,38), have established that this principal applies on a case-by-case basis to these individual genes. In the work presented here, we have extended these findings using genome-wide methodology to identify numerous additional genes that are regulated through this paradigm.…”
Section: Discussionmentioning
confidence: 99%
“…Furthermore, we identified inductive synergy between GR and NF-B at a novel enhancer within the TNFAIP3 locus and proposed a model in which cooperation between GR and NF-B at anti-inflammatory loci is central to the therapeutic effects of GCs. Subsequent studies by other researchers have supported this notion, with co-induction of IRAK3 (frequently referred to as IRAKM) and Sphk1 by GR and inflammatory stimuli linked to anti-inflammatory effects of GCs in various models of lung disease (37,38). Thus, cooperative gene induction mediated by convergence of activated GR and inflammatory signals at specific enhancers appears to contribute to the anti-inflammatory properties of GCs.…”
mentioning
confidence: 92%
“…This interaction induces transcription of various genes including sphingosine kinase 1 (Sphk1) and TGF-stimulated clone 22 domain protein-3 (Tsc22d3), the coding gene for GC-induced leucine zipper (GILZ) (56, 67). The latter protein is reported to bind to NF- κ B and AP-1, and the protective effect of this interaction has been shown in several inflammatory models (56).…”
Section: Glucocorticoids (Gcs) and The Glucocorticoid Receptor (Gr)mentioning
confidence: 99%