Although the anti-inflammatory effects of exogenous glucocorticoids (GC) upon inflammation are well recognized, the contribution of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), an amplifier of GC action in vivo, in modulating endogenous GC action during inflammation is unknown. Mouse models of arthritis and lung inflammation were used to explore the role of 11β-HSD1 in acute and chronic inflammation. Arthritis was induced in 11β-HSD1−/− (KO) and C57BL/6J (WT) male mice by intraperitoneal injection of arthritogenic serum from K/BxN transgenic mice. Clinical signs of inflammation were monitored over 21 d. Lung inflammation was induced by intrapleural injection of carrageenan, and inflammatory cells were recovered at 4 h and 24 h. The onset of arthritis occurred ∼1 d earlier in KO than in WT mice, and was slower to resolve in KO (50% reduction in clinical score of inflammation at 16 d in KO compared to 11 d in WT). Preliminary histological assessment revealed a reactive bone phenotype and intense periarticular inflammation (exostosis and ganglion formation) in KO compared to WT mice. Although both showed high basal (0800 h) plasma corticosterone levels 2 d following serum injection (253±39 nM and 218±61 nM, WT and KO, respectively), at 21 d plasma corticosterone was still elevated in KO (227±76 nM) while WT had returned to normal (86±27 nM). Following induction of acute lung inflammation, more cells were recovered in pleural lavages from KO than WT mice at 4 h (17×106 vs 9×106cells/ml, KO vs WT respectively, P<0.001) and 24 h following carrageenan injection (27×106 vs 18×106cells/ml, KO vs WT respectively, P=0.001). Interestingly, in KO at 4 h there was a lower proportion of apoptotic cells (3.7±0.8% vs 11.8±0.8%, KO vs WT respectively, P<0.001) and necrotic cells (5.7±2.0% vs 11.4±0.9% at 4 h, KO vs WT respectively, P<0.05), not seen at 24 h. Mice lacking 11β-HSD1 exhibit an exaggerated acute and chronic inflammatory response. Therefore, amplification of intracellular GC levels by 11β-HSD1 may be a critical anti-inflammatory mechanism to boost concentrations of endogenous active GC.
01 - 05 Apr 2006
European Society of Endocrinology