Background: Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFalpha levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice.
Results: Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFalpha in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFalpha and further increased serum corticosterone.
Conclusion: RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFalpha release, possibly due to the increased release of glucocorticoids.