title: Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids.
abstract: The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8(-/-) mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs in vitro and in vivo. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.
authors.affiliation: Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany. kirsten.lauber@med.uni-muenchen.de
authors.forename: K
authors.initials: K
authors.lastname: Lauber
authors.forename: H
authors.initials: H
authors.lastname: Keppeler
authors.forename: L E
authors.initials: LE
authors.lastname: Munoz
authors.forename: U
authors.initials: U
authors.lastname: Koppe
authors.forename: K
authors.initials: K
authors.lastname: Schröder
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: G
authors.initials: G
authors.lastname: Krönke
authors.forename: S
authors.initials: S
authors.lastname: Uderhardt
authors.forename: S
authors.initials: S
authors.lastname: Wesselborg
authors.forename: C
authors.initials: C
authors.lastname: Belka
authors.forename: S
authors.initials: S
authors.lastname: Nagata
authors.forename: M
authors.initials: M
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology*; D045744:Cell Line, Tumor; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics* / Q000378:metabolism*; D009895:Opsonin Proteins / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020298:U937 Cells
chemical_list: D000954:Antigens, Surface; D005938:Glucocorticoids; C098942:MFGE8 protein, human; D008894:Milk Proteins; D009895:Opsonin Proteins; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid