Abstract
Endogenous glucocorticoid action within cells is enhanced by prereceptor metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts intrinsically inert cortisone and 11-dehydrocorticosterone into active cortisol and corticosterone, respectively. 11β-HSD1 is highly expressed in immune cells elicited to the mouse peritoneum during thioglycollate-induced peritonitis and is down-regulated as the inflammation resolves. During inflammation, 11β-HSD1-deficient mice show enhanced recruitment of inflammatory cells and delayed acquisition of macrophage phagocytic capacity. However, the key cells in which 11β-HSD1 exerts these effects remain unknown. Here we have identified neutrophils (CD11b+,Ly6G+,7/4+ cells) as the thioglycollate-recruited cells that most highly express 11β-HSD1 and show dynamic regulation of 11β-HSD1 in these cells during an inflammatory response. Flow cytometry showed high expression of 11β-HSD1 in peritoneal neutrophils early during inflammation, declining at later states. In contrast, expression in blood neutrophils continued to increase during inflammation. Ablation of monocytes/macrophages by treatment of CD11b-diphtheria-toxin receptor transgenic mice with diphtheria toxin prior to thioglycollate injection had no significant effect on 11β-HSD1 activity in peritoneal cells, consistent with neutrophils being the predominant 11β-HSD1 expressing cell type at this time. Similar to genetic deficiency in 11β-HSD1, acute inhibition of 11β-HSD1 activity during thioglycollate-induced peritonitis augmented inflammatory cell recruitment to the peritoneum. These data suggest that neutrophil 11β-HSD1 increases during inflammation to contribute to the restraining effect of glucocorticoids upon neutrophil-mediated inflammation. In human neutrophils, lipopolysaccharide activation increased 11β-HSD1 expression, suggesting the antiinflammatory effects of 11β-HSD1 in neutrophils may be conserved in humans.
Highlights
Endogenous glucocorticoid action within cells is enhanced by prereceptor metabolism by 11hydroxysteroid dehydrogenase type 1 (11-HSD1), which converts intrinsically inert cortisone and 11-dehydrocorticosterone into active cortisol and corticosterone, respectively. 11-HSD1 is highly expressed in immune cells elicited to the mouse peritoneum during thioglycollate-induced peritonitis and is down-regulated as the inflammation resolves
We previously showed that 11-HSD1 activity is high in inflammatory cells recruited to the peritoneum during thioglycollateinduced peritonitis in mice and is down-regulated as the inflammation resolves [19]
The cells highly expressing 11-HSD1 recruited to the peritoneum during peritonitis are neutrophils
Summary
Compared with resident peritoneal cells (0 h), cellular expression of 11-HSD1 (measured as mean fluorescence intensity [MFI]) was increased in recruited cells 4 and 24 hours after thioglycollate injection but was reduced as the inflammation resolved, with used CD11b-DTR transgenic mice, in which the CD11b promoter drives the expression of the human diphtheria toxin receptor, to selectively ablate monocytes/macrophages Injection of diphtheria toxin 24 hours prior to thioglycollate markedly depleted monocytes/macrophages (Figure 3) but had no significant effect on 11-HSD1 activity in peritoneal cells lavaged 4 hours after the thioglycollate injection, consistent with neutrophils being the high 11-
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