Endocrine Abstracts (2009) 19 OC2

Anti-inflammatory effects of 5 alpha-reduced glucocorticoids in vitro and in vivo

C Yang1, A Rossi2, R Duffin2, D Livingstone1, C Kenyon1, B Walker1 & R Andrew1

1Centre for Cardiovascular Science, Edinburgh, UK; 2Centre for Inflammation Research, Edinburgh, UK.

Previously, we have shown that 5α-tetrahydrocorticosterone (5αTHB), the reduced metabolite of corticosterone (B, the main glucocorticoid in rodents), binds to the glucocorticoid receptor, suppresses the HPA axis but has weak in vivo effects on adipose tissue and liver metabolism. Here we have compared the anti-inflammatory effects of B and 5αTHB in three in vitro and in vivo experiments. Cytokine release was measured by cytometric bead array. Values are mean±S.E.M. Significant differences from control are indicated by *P<0.05, **P<0.01 and ***P<0.001.

Experiment 1. Bone marrow-derived murine macrophages were primed (1 h) with vehicle or 1 μM B or 1 μM 5αTHB before stimulation with lipopolysaccharide (LPS, 100 ng/ml, 24 h). B and 5αTHB enhanced IL-10 secretion (32.3±9.1* and 59.5±9.0** vs <17.5 pg/ml) from unstimulated macrophages and reduced secretion of TNFα (80.7±2.1*** and 243.8±24.2*** vs 312.3±25.6 pg/ml) and IL-6 (1.42±0.04*** and 3.87±0.05* vs 4.62±0.07 ng/ml) following stimulation with LPS.

Experiment 2. Male C57BL/6 mice (8–10 weeks, n=12) were infused sc with vehicle or 50 μg B/d or 50 μg 5αTHB/d for 2 weeks. After cull whole blood was collected and stimulated with LPS (0.1–100 ng/ml). Treatment with both B and 5α-THB suppressed LPS-induction of TNFα (**B, ** 5α-THB) and IL-6 (*B; 5αTHB: P=0.09).

Experiment 3. Mice were injected sc with vehicle or 0.1 mg B or 0.1 mg 5αTHB. One hour later, peritonitis was induced by LPS (10 mg/kg). Cytokines were measured in peritoneal fluid collected by lavage. Eighteen hours after LPS treatment, IL-6 was reduced in fluid from B and 5α-THB-treated mice compared with vehicle controls (12.4±1.2** and 15.0±4.4* vs 25.6±3.3 pg/ml).

We conclude that 5α-THB has anti-inflammatory properties similar to those of corticosterone. Given previously reported weaker metabolic effects, 5αTHB could be a prototype for a selective anti-inflammatory drug with limited metabolic toxicity. Contrary to current dogma, it is unlikely that 5α-reduction is simply an inactivating pathway for glucocorticoids.

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