In vitro dissection of anti-diabetic effects of compound a, a dissociating glucocorticoid receptor ligand

Abstract

Compound A (CpdA), or 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethyl-ammonium chloride, is a stable analog of the hydroxyl phenyl aziridine precursor found in the Namibian shrub Salsola tuberculatiformis Botschantzev. It belongs to the group of so-called ``dissociated{''} GC receptor ligands that downmodulate pro-inflammatory gene expression via the transrepression mechanism, but without physically binding to DNA. We have recently reported that the in vivo administration of CpdA exerts a strong protective effect in a pharmacological model of type 1 diabetes in mice. The goal of this study was to investigate in more detail the effects of CpdA on multiple immune system components, as well as on target pancreatic beta cells in direct in vitro exposure. The utility of CpdA in diabetes prevention was evaluated through its addition to mitogen-activated spleen, lymph node and peritoneal cells of C57BL/6 mice, and to murine pancreatic islets and INS-1 and RINm5F beta cell lines. CpdA modulated immune cell-derived cytokine production in vitro by restraining the pro-inflammatory M1/Th1/Th17 response and switching it towards an anti-inflammatory Th2 profile. However, it did not preserve beta cells from the cytotoxic action of inflammatory cytokines. Thus, the anti-diabetic properties of CpdA are mediated through the modulation of immune cell differentiation pathways rather than through rescue of target cells from autoimmune attack.