Regulation of S100A8 by Glucocorticoids

Abstract

S100A8 (A8) has roles in inflammation, differentiation and development and is associated with oxidative defense. Murine A8 (mA8) is up-regulated in macrophages, fibroblasts, and microvascular endothelial cells by LPS. Glucocorticoids (GCs) amplified LPS-induced mA8 in these cells. Relative to stimulation by LPS, GCs increased mA8 gene transcription and mRNA half-life. Enhancement required new protein synthesis, IL-10 and products of the cyclooxygenase-2 pathway, and both ERK1/2 and p38 MAPK. Protein kinase A positively and protein kinase C negatively regulated this process. Promoter analysis indicated element(s) essential for LPS and dexamethasone enhancement colocated within the region −178 to 0 bp. In the absence of glucocorticoid response elements, NF1 motif at −58 is a candidate for mediation of enhancement. Gel shift analysis detected no differences between LPS- and LPS/dexamethasone-treated complexes within this region. GCs increased constitutive levels of A8 and S100A9 (A9) mRNA in human monocytes. The synovial membrane of rheumatoid patients treated with high dose i.v. methylprednisolone contained higher numbers of A8/A9-positive macrophages than pre- or posttreatment samples. Results support the proposal that A8 has anti-inflammatory properties that may be independent of hetero-complex formation with A9 and may also enable localized defense in the absence of overriding deleterious host responses.

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

“…Known as the endogenous Toll-like receptor 4 agonist (20), S100A8 has been shown to be regulated by glucocorticoids upon LPS stimulation (21). In our study, we found that transcriptional activation of HIF-1 in myeloid cells regulates S100A8 (Fig.…”

S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer

“…Stability of the S100A7 mRNA and protein are unknown but may be a factor in this persistence. The closely related S100A8 gene shows an mRNA half life of B8 h that can be increased up to 20 h by glucocorticoid treatment (Hsu et al, 2005). Similarly, S100A4 mRNA and protein half life has been shown to be B8 h and B85 h, respectively (Rivard et al, 2007).…”

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

“…Medium and mediators were only used if endotoxin levels were Ͻ20 pg/ml (chromogenic Limulus amebocyte assay; Associates of Cape Cod) (4,29). Bovine calf serum (HyClone) had been pretested before purchase.…”

“…Human monocytes isolated from peripheral blood of healthy subjects as previously described (29) were analyzed using a Beckman Coulter counter. Preparations generally contained ϳ10% monocytes, ϳ90% lymphocytes, and Ͻ1.5% granulocytes.…”

“…Clinical observations indicate that a diminished capacity to produce IL-10 is associated with improved viral clearance and antiviral immunity can be promoted by targeting the IL- Our earlier studies showed that S100A8 expression in murine macrophages induced by LPS is a late-phase response that is neutralized by anti-IL-10 Abs, although IL-10 does not directly induce the gene (28). Moreover, corticosteroids potentiate S100A8 induction by LPS in an IL-10-dependent manner (29), suggesting that S100A8 may have anti-inflammatory properties. IL-10 down-regulates release of reactive oxygen and nitrogen species in macrophages (30) and this may be facilitated by S100A8, which we showed to be a potent scavenger of peroxide and hypochlorite generated by the myeloperoxidase system (31).…”