title: Glucocorticoids induce apoptosis in human monocytes: potential role of IL-1 beta.
abstract: Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on a variety of immune cells, including monocytes and macrophages. However, the exact cellular mechanisms underlying this anti-inflammatory capacity are still unknown. In our study, we determined the induction of apoptosis by GC in human monocytes. Peripheral blood monocytes were isolated by density centrifugation methods with a purity of >90% and were cultured in RPMI 1640 medium. Monocyte apoptosis was determined by four independent methods, including annexin-V staining, TUNEL, DNA-laddering, and typical morphology by means of transmission electron microscopy. TNF-alpha and IL-1beta were measured by ELISA. GC receptor was blocked with mifepristone. Caspase 3 was inhibited with caspase-3 inhibitor (DEVD-CHO). Stimulation with different GC at therapeutic concentrations resulted in monocyte apoptosis in a time- and dose-dependent manner. Necrosis was excluded by propidium iodide staining. Proinflammatory cytokines such as IL-1beta and TNF-alpha were down-regulated by GC treatment. Continuous treatment of monocytes with IL-1beta, but not with TNF-alpha, could almost completely prevent GC-induced cell death. The addition of mifepristone or caspase-3 inhibitor could partially abrogate GC-induced apoptosis as well as GC-induced inhibition of IL-1beta. This is the first study to demonstrate induction of apoptosis by GC in human monocytes. GC-induced monocyte apoptosis may be partially mediated through effects on IL-1beta production. It is conceivable that GC exert their anti-inflammatory capacity in various diseases, at least in part, by the induction of apoptosis in monocytes.
authors.affiliation: Department of Medicine B, Institute for Immunology, University of Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.forename: H G
authors.initials: HG
authors.lastname: Pauels
authors.forename: N
authors.initials: N
authors.lastname: Lügering
authors.forename: A
authors.initials: A
authors.lastname: Lügering
authors.forename: W
authors.initials: W
authors.lastname: Domschke
authors.forename: T
authors.initials: T
authors.lastname: Kucharzik
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D053148:Caspase 3; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D004396:Coloring Agents; D003907:Dexamethasone / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D011419:Propidium; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D061945:Caspase Inhibitors; D004396:Coloring Agents; D004338:Drug Combinations; D005938:Glucocorticoids; D007375:Interleukin-1; D009842:Oligopeptides; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C108637:aspartyl-glutamyl-valyl-aspartal; D015735:Mifepristone; D011419:Propidium; D003907:Dexamethasone; C505407:CASP3 protein, human; D053148:Caspase 3