title: 11β-Hydroxysteroid Dehydrogenase Type 1 Is Expressed in Neutrophils and Restrains an Inflammatory Response in Male Mice.
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.
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Agnes E
authors.initials: AE
authors.lastname: Coutinho
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Tiina M J
authors.initials: TM
authors.lastname: Kipari
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Zhenguang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Esteves
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lucas
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: James S
authors.initials: JS
authors.lastname: Gilmour
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: John S
authors.initials: JS
authors.lastname: Savill
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: Centre for Cardiovascular Science (A.E.C., T.M.J.K., Z.Z., C.L.E., J.S.G., S.P.W., B.R.W., J.R.S., K.E.C.) and Medical Research Council Centre for Inflammation Research (A.E.C., C.D.L., J.S.G., J.H., J.S.S., A.G.R.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism*
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1