4664 total record number 37 records this year

Glucocorticoid augments lipopolysaccharide-induced activation of the IB-dependent genes encoding the anti-microbial glycoproteins lipocalin 2 and pentraxin 3

Yamazaki, S;Akira, S;Sumimoto, H;

Bacterial lipopolysaccharide (LPS), one of the most potent inducers of inflammation, activates the transcription factor NF-B to induce expression of both proinflammatory mediators and anti-microbial glycoproteins such as lipocalin 2 (Lcn2) and pentraxin 3 (PTX3) in macrophages. Glucocorticoids are known to inhibit LPS-induced expression of proinflammatory cytokines via glucocorticoid receptor (GR)-mediated transrepression of NF-B, whereas their effect on induction of anti-microbial effectors has remained to be elucidated. Here we show that the synthetic glucocorticoid dexamethasone (Dex) strongly enhances LPS-induced transcription of Lcn2 and Ptx3, although Dex by itself fails to trigger their transcription. In macrophages deficient in IB (an inducible coactivator of NF-B), Lcn2 and Ptx3 are not activated by LPS either alone or in combination with Dex. Association of GR as well as Brg1 (a subunit of the chromatin remodelling Swi/Snf complex) with a functional glucocorticoid response element in Lcn2 requires both the costimulation with LPS and the presence of IB. Although Ptx3 does not contain the element, LPS induces recruitment of Dex-liganded GR to NF-B-binding sites in regulatory regions of Ptx3, an event that does not occur in IB-deficient macrophages. Thus glucocorticoids likely regulate infection-induced inflammation by increasing anti-microbial effectors in an IB-dependent manner, while repressing proinflammatory genes.