title: Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium.
abstract: BACKGROUND
  Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumour necrosis factor (TNF) family member capable of inducing apoptosis in many cell types.
  
  
  METHODS
  Using immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) and real-time PCR we investigated the expression of TRAIL, TRAIL receptors and several key molecules of the intracellular apoptotic pathway in human synovial tissues from various types of arthritis and normal controls. Synovial tissues from patients with active rheumatoid arthritis (RA), inactive RA, osteoarthritis (OA) or spondyloarthritis (SpA) and normal individuals were studied.
  
  
  RESULTS
  Significantly higher levels of TRAIL, TRAIL R1, TRAIL R2 and TRAIL R4 were observed in synovial tissues from patients with active RA compared with normal controls (p < 0.05). TRAIL, TRAIL R1 and TRAIL R4 were expressed by many of the cells expressing CD68 (macrophages). Lower levels of TUNEL but higher levels of cleaved caspase-3 staining were detected in tissue from active RA compared with inactive RA patients (p < 0.05). Higher levels of survivin and x-linked inhibitor of apoptosis protein (xIAP) were expressed in active RA synovial tissues compared with inactive RA observed at both the protein and mRNA levels.
  
  
  CONCLUSIONS
  This study indicates that the induction of apoptosis in active RA synovial tissues is inhibited despite stimulation of the intracellular pathway(s) that lead to apoptosis. This inhibition of apoptosis was observed downstream of caspase-3 and may involve the caspase-3 inhibitors, survivin and xIAP.
authors.affiliation: Discipline of Pathology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, North Terrace, Adelaide, 5005 South Australia, Australia. a.dharmapatni@adelaide.edu.au
authors.forename: Anak A S S K
authors.initials: AA
authors.lastname: Dharmapatni
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Smith
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Holding
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ahern
authors.forename: Helen
authors.initials: H
authors.lastname: Weedon
authors.forename: Paul
authors.initials: P
authors.lastname: Chen
authors.forename: Gavin
authors.initials: G
authors.lastname: Screaton
authors.forename: Xiao N
authors.initials: XN
authors.lastname: Xu
authors.forename: David R
authors.initials: DR
authors.lastname: Haynes
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human