title: Local amplification of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes.
abstract: Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) modulates cellular steroid action. 11beta-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11beta-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1, as 11beta-HSD1 mRNA, but not 11beta-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1(-/-) macrophages, and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1(-/-) mice. These data point to an early role for 11beta-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Sciences, Centre for Cardiovascular Sciences, The Queen's Medical Research Institute, University of Edinburgh, UK.
authors.forename: James S
authors.initials: JS
authors.lastname: Gilmour
authors.forename: Agnes E
authors.initials: AE
authors.lastname: Coutinho
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cailhier
authors.forename: Tak Yung
authors.initials: TY
authors.lastname: Man
authors.forename: Michael
authors.initials: M
authors.lastname: Clay
authors.forename: Graham
authors.initials: G
authors.lastname: Thomas
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Harris
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: John S
authors.initials: JS
authors.lastname: Savill
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001202:Ascitic Fluid / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D010538:Peritonitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D013864:Thioglycolates / Q000008:administration & dosage; D015854:Up-Regulation / Q000276:immunology
chemical_list: D013864:Thioglycolates; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone