Genomic response of human immune and non-immune cells to glucocorticoids

Authors

• MR Gadkari
• KN Howe
• LM Franco
• P Kumar
• J Tsang
• RN Germain

Abstract

Glucocorticoids are the most effective, cost-effective, and widely used class of immunosuppressive and anti-inflammatory medications. However, significant gaps exist in our understanding of their clinical actions, particularly as it relates to cell-lineage-specific effects and the effects that are shared among biological systems versus those that are unique to the immune system. This knowledge could help inform the development of therapeutic strategies that preserve the rapid and potent activity of glucocorticoids while minimizing untoward effects. We have studied the genomic response of human primary hematopoietic and non-hematopoietic cells exposed in vitro to methylprednisolone, with a combination of total-RNA and small-RNA sequencing. Our initial results suggest that the genomic response to glucocorticoids is highly cell-specific, and that the pathways and genes most affected are significantly different between immune and non-immune cells. We have extended this research to a clinical study of healthy subjects ages 18-64 (n=20). Subjects received a single intravenous dose of 250 mg of methylprednisolone, and blood and skin biopsies were collected before and at 2 and 4 hours post-infusion. Blood samples were processed for isolation of six hematopoietic cell sub-populations (neutrophils, B cells, CD4+ T cells, CD8+ T cells, monocytes, and NK cells). Total RNA will be purified from each cell sub-population and from skin biopsies for total-RNA and small-RNA sequencing. At the completion of this study we expect to significantly expand our knowledge of the cell-type and immune-specific genomic actions of glucocorticoids in humans.

Scientific Focus Area: Genetics and Genomics

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