Glucocorticoid induced gene-regulation in murine bone marrow derived monocytes.. Mus musculus

Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsM interact with T-cells in suppressing proliferation as well as cytokine release of CD8+ and especially CD4+ T-cells in vitro, and that they support generation of Foxp3+ cells. We therefore tested their immunosuppressive potential in CD4+ T-cell-induced colitis in vivo. We found that injection of GCsM into mice with already established severe colitis abolishes the inflammation and results in significant clinical improvement within a few days. T-cells recovered from GCsM-treated mice reveal reduced secretion of pro-inflammatory cytokines IFN- or IL-17. Furthermore, accumulation of clusters of Foxp3+ CD4+ T-cells were detectable at local sites of inflammation in their colon. Thus, GCsM are able to modify T-cell responses in vitro and in vivo and are able to down-regulate and clinically cure an established severe T-cell mediated colitis. Overall design: Bone marrow derived monocytes where cultured 16 h with media containing M-CSF (control monocytes) or media containing M-CSF and dexamethasone (GCsM). In three independent experiments, total RNA from GCsM and control monocytes was isolated and processed for microarray hybridization.