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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 thioglycollaterecruited 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.
Author(s): Coutinho AE, Kipari TMJ, Zhang Z, Esteves CL, Lucas CD, Gilmour JS, Webster SP, Walker BR, Hughes J, Savill JS, Seckl JR, Rossi AG, Chapman KE
Publication type: Article
Publication status: Published
Journal: Endocrinology
Year: 2016
Volume: 157
Issue: 7
Pages: 2928-2936
Print publication date: 01/07/2016
Online publication date: 01/07/2016
Acceptance date: 27/04/2016
ISSN (print): 0013-7227
ISSN (electronic): 1945-7170
Publisher: Endocrine Society
URL: https://doi.org/10.1210/en.2016-1118
DOI: 10.1210/en.2016-1118
PubMed id: 27145012
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