Tumor necrosis factor alpha activates release of B lymphocytestimulator by neutrophils infiltrating the rheumatoid joint

Lakhvie Assi, See Wong, A Ludwig, Karim Raza, Caroline Gordon, Michael Salmon, Janet Lord, Dagmar Scheel-Toellner

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55 Citations (Scopus)
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Objective. The tumor necrosis factor (TNF) family member B lymphocyte stimulator (BLyS) is an important regulator of B cell-dependent autoinummity. Similar to other TNF family members, it is generally expressed as a transmembrane protein and cleaved from the surface to release its active soluble form. This study was undertaken to investigate the expression of BLyS and regulation of BLyS release from the surface of neutrophils infiltrating the rheumatoid joint. Methods. BLyS expression was studied in neutrophils from the synovial fluid and peripheral blood of patients with rheumatoid arthritis (RA) and healthy controls, by flow cytometry, Western blotting, and immunofluorescence analyses. Peripheral blood neutro-phils cultured with 50% RA synovial fluid were study for membrane expression of BLyS. Neutrophils were exposed to a range of proinflammatory cytokines to study the mechanisms of surface loss of BLyS. Results. Expression of BLyS was detected on the surface of peripheral blood neutrophils from both RA patients and healthy controls, whereas BLyS expression on synovial fluid neutrophils was very low. Constitutive expression of BLyS was observed in neutrophils, both on the cell membrane and in intracellular stores; however, BLyS release from each of these sites was found to be regulated independently. Of the various cytokine stimuli, only TNF alpha triggered release of BLyS from the neutrophil membrane. This process led to release of physiologically relevant quantities of soluble BLyS, which was dependent on the presence of the pro-protein convertase furin. In contrast, stimulation of neutrophils with granulocyte colony-stimulating factor induced BLyS release from the intracellular stores. Incubation of peripheral blood neutrophils with RA synovial fluid led to TNF alpha-dependent shedding of BLyS from the cell surface. Conclusion. These findings indicate that as neutrophils enter the site of inflammation, they release surface-expressed BLyS in a TNFa-dependent manner, and thus may contribute to local stimulation of autoimmune B cell responses.
Original languageEnglish
Pages (from-to)1776-1786
Number of pages11
JournalArthritis & Rheumatism
Issue number6
Publication statusPublished - Jun 2007


  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid
  • Autoimmunity
  • B-Cell Activating Factor
  • B-Lymphocytes
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Furin
  • Gene Expression Regulation
  • Granulocyte Colony-Stimulating Factor
  • Humans
  • Inflammation
  • Male
  • Middle Aged
  • Neutrophils
  • Synovial Fluid
  • Tumor Necrosis Factor-alpha


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