Abstract
BackgroundGlucocorticoids 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 TNFα levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice.ResultsChronic 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 TNFα 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 TNFα and further increased serum corticosterone.ConclusionRU486 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 TNFα release, possibly due to the increased release of glucocorticoids.
Highlights
Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses
The db/db mice had significantly higher levels of serum corticosterone, similar levels of adrenocorticotropic hormone (ACTH), and higher expression levels of hepatic glucogenesis enzyme phosphenolpyruvate carboxykinase (PEPCK) and glucose-6phosphatase (G6Pase) genes compared with the C57BL/ 6J lean litter mates (Fig 1 and Table 1)
The current study demonstrated that chronic treatment with glucocorticoid receptor (GR) antagonist RU486 for 10 days dose-dependently decreased postprandial blood glucose, increased serum corticosterone and ACTH, and did not affect serum MCP1 and IL-6, in db/db mice
Summary
Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. Various clinical and pre-clinical investigations have indicated that antagonists of the glucocorticoid receptor (GR) could be useful in the treatment of diabetes [1,2] and depression [3], but concerns about the effects of GR antagonists on the body's ability to regulate inflammatory responses [4] have hampered development of GR antagonists for these indications. Activation of the GR with endogenous glucocorticoids (GCs) is the body's primary method for suppression of the inflammatory response [5]. BMC Pharmacology 2008, 8:7 http://www.biomedcentral.com/1471-2210/8/7 prevent an overly strong response to an ongoing localized inflammatory process [7]. Disruption of this response due to exhaustion of the adrenal cortex results in septic shock. In the treatment of septic shock, low doses of GCs have therapeutic effects by correcting adrenal cortex exhaustion, exerting appropriate anti-inflammatory properties, and enhancing endogenous catecholamine effects [8]
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