Research article

Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium

Anak ASSK Dharmapatni¹ , Malcolm D Smith² , David M Findlay³ , Christopher A Holding¹ , Andreas Evdokiou³ , Michael J Ahern² , Helen Weedon² , Paul Chen⁴ , Gavin Screaton⁵ , Xiao N Xu⁴ and David R Haynes¹

¹  Discipline of Pathology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, North Terrace, Adelaide, 5005 South Australia, Australia

²  Rheumatology Research Unit, Repatriation General Hospital, Daws Road, Adelaide, 5041 South Australia, Australia

³  Discipline of Orthopaedics and Trauma, School of Medicine, Faculty of Health Sciences, University of Adelaide and Hanson Institute, Frome Road, Adelaide, 5005 South Australia, Australia

⁴  MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3, UK

⁵  Hammersmith Hospital, Du Cane Road, London W12 0NN, UK

author email corresponding author email

Arthritis Research & Therapy 2009, 11:R13doi:10.1186/ar2603

Published:	27 January 2009

Abstract

Introduction

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.