Immune regulation by glucocorticoids can be linked to cell-lineage-specific transcriptional responses

Abstract

Abstract Glucocorticoids remain the most widely used class of immunosuppressive and anti-inflammatory drugs, yet significant gaps exist in our understanding of glucocorticoid-mediated immunoregulation. We have studied the transcriptional response to glucocorticoids, by total RNA sequencing and small-RNA sequencing, in nine human primary cell populations: B cells, CD4+ T cells, monocytes, neutrophils, endothelial cells, myoblasts, osteoblasts, fibroblasts, and preadipocytes. Our results suggest that the human response to glucocorticoids displays cell-lineage dependency, in terms of the individual genes and pathways that are differentially affected, as well as the magnitude and direction of transcriptional regulation. While decreased expression of genes that function in critical immune pathways is widespread, increased expression of negative regulators of immune activation is also common. Despite the critical role of B cells in many diseases for which glucocorticoids are used, glucocorticoid effects on human B cells are particularly poorly understood. We have identified significant transcriptional and functional changes in key molecules involved in B cell receptor signaling, intracellular Toll-like receptor signaling, B cell activation, differentiation, and antibody production. We have validated these results at the RNA and protein levels in vivo, by assaying B cells isolated from healthy human volunteers given a single intravenous dose of a glucocorticoid. Overall, our results illustrate the ability of an unbiased, genome-wide approach to uncover previously undescribed, cell-type-dependent transcriptional responses that can be linked to the immunoregulatory actions of glucocorticoids in humans.