Repository corticotrophin injection exerts direct acute effects on human B cell gene expression distinct from the actions of glucocorticoids

Summary Repository corticotrophin injection (RCI, H.P Acthar® gel) has been approved for use in the management of multiple autoimmune and inflammatory diseases for more than a half‐century, but its mechanism of action is not well understood. We used RNA‐Seq methods to define RCI‐regulated mRNAs in cultured human B cells under conditions of activation by interleukin (IL)‐4 and CD40 ligand. Following IL‐4/CD40L activation and RCI treatment we found up‐regulation of 115 unique mRNA transcripts and down‐regulation of 80 unique mRNAs. The effect on these RNA levels was dose‐dependent for RCI and was distinct from changes in mRNA expression induced by treatment with a potent synthetic glucocorticoid. RCI down‐regulated mRNAs were observed to include a significant over‐representation of genes critical for B cell proliferation under activating conditions. These data confirm that RCI exerts direct effects on human B cells to modulate mRNA expression in specific pathways of importance to B cell function and that, at the molecular level, the effects of RCI are distinct from those exerted by glucocorticoids. Repository corticotropin injection (RCI) has been used clinically for treatment of autoimmune disorders but its mechanism of action has not been understood. This manuscript identifies direct actions of RCI on isolated human B cells activated in culture with IL4 and CD40 ligand. RCI effects on gene expression in B cells under such conditions included suppression of a variety of genes involved in known immune response pathways.