title: Anti-tumor necrosis factor α targets protein kinase B/c-Akt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis.
abstract: OBJECTIVE
  To determine whether therapeutic strategies that block interleukin-6 (IL-6) or tumor necrosis factor α (TNFα) can improve the responsiveness of Teff cells to suppression in patients with juvenile idiopathic arthritis (JIA).
  
  
  METHODS
  Synovial fluid mononuclear cells (SFMCs) from the inflamed joints of patients with JIA were cultured in the presence of etanercept or anti-IL-6 in vitro, and protein kinase B (PKB)/c-Akt activation and responsiveness to suppression were measured. In addition, the in vivo effects of TNFα blockade were investigated using peripheral blood mononuclear cells obtained from patients before and after the start of etanercept therapy.
  
  
  RESULTS
  In vitro treatment of SFMCs with anti-IL-6 led to improved Treg cell-mediated suppression of cell proliferation in some but not all patients. Blocking TNFα with etanercept, however, clearly enhanced suppression, especially that of CD8+ T cells. In the presence of etanercept, PKB/c-Akt activation of Teff cells was reduced, and cells became more susceptible to transforming growth factor β-mediated suppression, indicating that anti-TNFα directly targets resistant Teff cells.
  
  
  CONCLUSIONS
  This study is the first to show that anti-TNFα targets the resistance of Teff cells to suppression, resulting in improved regulation of inflammatory effector cells.
authors: Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Ellen J
authors: EJ
authors: Wehrens
authors: Sebastiaan J
authors: SJ
authors: Vastert
authors: Gerdien
authors: G
authors: Mijnheer
authors: Jenny
authors: J
authors: Meerding
authors: Mark
authors: M
authors: Klein
authors: Nico M
authors: NM
authors: Wulffraat
authors: Berent J
authors: BJ
authors: Prakken
authors: Femke
authors: F
authors: van Wijk
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
chemical_list: D018501:Antirheumatic Agents; D000068800:Etanercept; D007074:Immunoglobulin G; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors