title: Differential expression of factors involved in the intrinsic and extrinsic apoptotic pathways in juvenile systemic lupus erythematosus.
abstract: Dysregulated neutrophil apoptosis may result in the development of autoimmune disease by contributing to nuclear autoantigen exposure, leading to autoantibody generation and a breakdown in immune tolerance. It has previously been shown that neutrophil apoptosis is increased in juvenile-onset systemic lupus erythematosus (JSLE). This study aims to investigate the pathways involved in JSLE serum-induced apoptosis. Caspases 3, 7-9, IAP1/2, XIAP and FADD mRNA levels and TRAIL R2, BID/tBID, caspase 8 and 9 protein expression were measured in neutrophils from JSLE patients (n = 14) and controls (n = 10). The mRNA levels of caspases 7-9 were significantly higher in JSLE neutrophils than in controls, whereas the mRNA levels of IAP1, IAP2 and XIAP were decreased (p < 0.05). A decrease in neutrophil apoptosis induced by JSLE serum was observed in the presence of caspase 8 and 9 inhibitors (p < 0.05), and the activity of caspases 8 and 9 increased over time. tBID protein expression increased following incubation with JSLE serum. These data focus specifically on the expression and activity of the main caspases in the intrinsic and extrinsic apoptotic pathways. Increased expression of factors involved in the downstream signalling of the extrinsic apoptotic pathway indicates a prominent involvement of this pathway in JSLE serum-induced apoptosis.
authors.affiliation: Institute of Child Health, Alder Hey Children's NHS Foundation Trust, Liverpool University, Liverpool, UK. angela.fahey@liv.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Midgley
authors.forename: K
authors.initials: K
authors.lastname: Mayer
authors.forename: S W
authors.initials: SW
authors.lastname: Edwards
authors.forename: M W
authors.initials: MW
authors.lastname: Beresford
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000276:immunology; D002648:Child; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000276:immunology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D061945:Caspase Inhibitors; D053200:Fas-Associated Death Domain Protein; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases