Endocrine Abstracts

Meningitis is associated with high mortality and morbidity predominantly driven by meningeal inflammation. Herpes Simplex virus (HSV) is a major cause of viral meningitis typically progressing to HSV encephalitis. Numerous studies highlight the importance of glucocorticoids in lowering inflammation in bacterial meningitis, but very limited data exists on the use of glucocorticoids in viral meningitis. We aimed to characterise 11β-HSD1 (which interconverts inactive cortisone to active cortisol) in meningeal cells, and evaluate the role of glucocorticoids in modulating inflammation.

An in-vitro model of meningeal infection was established using human meningeal fibroblasts (HMF) primary cells. Treatments with toll like receptor (TLR) ligands, which mimic pathogen associated infection, were used to initiate an immune response.

RT-PCR analysis of HMF defined mRNA expression of 11β-HSD1, glucocorticoid receptor, mineralocorticoid receptor, hexose-6-phosphate dehydrogenase and TLRs 1-6 and 8–10. Following 24 h treatment with TLR ligands (1–10), the TLR3 ligand poly(I:C), which mimics HVS infection, significantly up-regulated the pro-inflammatory cytokine IL-8 (60 672±9167 versus control 10 596±1980 pg/ml, P<0.001). In addition, poly(I:C) significantly increased 11β-HSD1 oxo-reductase activity (0.59±0.01 pmol/mg per h versus control (0.00 pmol/mg per h, P<0.001). Twenty-four hours treatment with IL-1β produced a similar result, significantly increasing IL-8 production (26 279±3455 versus control 10 596±1980 pg/ml, P<0.05) and upregulating 11β-HSD1 activity (0.84±0.10 pmol/mg per h versus control 0.00 pmol/mg per h, P<0.001). Twenty-four hours incubation with poly(I:C) and glucocorticoids (dexamethasone (1×10⁻⁹–10⁻⁵ M), cortisol (1×10⁻⁹–10⁻⁷ M) and cortisone (1×10⁻⁷ M)) significantly reduced IL-8 production (P<0.001, P<0.01 and P<0.01 respectively).

We have identified HMF as a novel glucocorticoid target tissue which up-regulates local cortisol production, via 11β-HSD1, in the presence of HSV ligand. Additionally, glucocorticoids significantly reduce TLR3 (HSV) driven inflammation in HMF. 11β-HSD1 may have a protective role in viral meningitis and further evaluation of the therapeutic role of glucocorticoids is now warranted.