Premium
Brief Report: Autocrine Cytokine–Mediated Deficiency of TRAIL‐Induced Monocyte Apoptosis in Rheumatoid Arthritis
Author(s) -
Meusch Undine,
Klingner Maria,
Mathar Christoph,
Malysheva Olga,
Baerwald Christoph,
Rossol Manuela,
Wagner Ulf
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39138
Subject(s) - apoptosis , tumor necrosis factor alpha , monocyte , proinflammatory cytokine , medicine , autocrine signalling , rheumatoid arthritis , immunology , cytokine , signal transduction , arthritis , interleukin , cancer research , receptor , inflammation , biology , microbiology and biotechnology , biochemistry
Objective Dysregulated apoptosis of monocytes is a pathogenic feature of rheumatoid arthritis (RA). The aim of this study was to investigate the role of TRAIL and TRAIL‐induced apoptosis in patients with RA. Methods Cell surface expression and serum concentrations of TRAIL were determined in 63 patients with RA, and TRAIL‐induced monocyte apoptosis was quantified. Surface expression of TRAILR‐1, TRAILR‐2, TRAILR‐3, TRAILR‐4, CXCR1, and CXCR2 was determined, and intracellular signal transduction was investigated. In 8 patients with RA, clinical and laboratory parameters of disease activity were investigated longitudinally, before and after initiation of treatment with tumor necrosis factor (TNF) inhibitors. Results Serum concentrations of both TRAIL and interleukin‐8 (IL‐8) were increased in patients with RA, while cell surface expression of the TRAIL receptors TRAILR‐1, TRAILR‐2, TRAILR‐3, and TRAILR‐4 was diminished. TRAIL‐induced monocyte apoptosis was significantly decreased in RA due to increased TRAIL‐induced IL‐8 secretion by RA monocytes. The combined effect of TRAIL and IL‐8 on monocytes resulted in activation of antiapoptotic pathways, including p42/44 MAPK and p38. Susceptibility to TRAIL‐induced apoptosis was restored in RA monocytes after 3 months of TNF inhibition. Conclusion In RA, circulating monocytes with the potential to produce proinflammatory cytokines appear to have defects in several pathways of apoptosis induction, among which is a deficiency in TRAIL‐induced apoptosis. Although this resistance to apoptosis might contribute to perpetuation of the disease, it remains to be determined whether specific induction of apoptosis could be therapeutically beneficial.