title: Brief Report: Autocrine Cytokine-Mediated Deficiency of TRAIL-Induced Monocyte Apoptosis in Rheumatoid Arthritis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Undine
authors.initials: U
authors.lastname: Meusch
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Klingner
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mathar
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Malysheva
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Baerwald
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rossol
authors.affiliation: University of Leipzig, Leipzig, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Wagner
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000473:pathology* / Q000503:physiopathology*; D019898:Autocrine Communication / Q000502:physiology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009000:Monocytes / Q000473:pathology* / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016209:Interleukin-8; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases