title: Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus.
abstract: BACKGROUND
  Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. The heterodimer of the cytosolic calcium-binding proteins S100A8 and S100A9 (S100A8/A9) is secreted by activated polymorphonuclear neutrophils (PMNs) and monocytes and serves as a serum marker for several inflammatory diseases. Furthermore, S100A8 and S100A9 have many pro-inflammatory properties such as binding to Toll-like receptor 4 (TLR4). In this study we investigated if aberrant cell surface S100A8/A9 could be seen in SLE and if plasmacytoid dendritic cells (pDCs) could synthesize S100A8/A9.
  
  
  METHODS
  Flow cytometry, confocal microscopy and real-time PCR of flow cytometry-sorted cells were used to measure cell surface S100A8/A9, intracellular S100A8/A9 and mRNA levels of S100A8 and S100A9, respectively.
  
  
  RESULTS
  Cell surface S100A8/A9 was detected on all leukocyte subpopulations investigated except for T cells. By confocal microscopy, real-time PCR and stimulation assays, we could demonstrate that pDCs, monocytes and PMNs could synthesize S100A8/A9. Furthermore, pDC cell surface S100A8/A9 was higher in patients with active disease as compared to patients with inactive disease. Upon immune complex stimulation, pDCs up-regulated the cell surface S100A8/A9. SLE patients had also increased serum levels of S100A8/A9.
  
  
  CONCLUSIONS
  Patients with SLE had increased cell surface S100A8/A9, which could be important in amplification and persistence of inflammation. Importantly, pDCs were able to synthesize S100A8/A9 proteins and up-regulate the cell surface expression upon immune complex-stimulation. Thus, S100A8/A9 may be a potent target for treatment of inflammatory diseases such as SLE.
authors.affiliation: Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Sölvegatan 23, 223 62 Lund, Sweden. christian.lood@med.lu.se
authors.forename: Christian
authors.initials: C
authors.lastname: Lood
authors.forename: Martin
authors.initials: M
authors.lastname: Stenström
authors.forename: Helena
authors.initials: H
authors.lastname: Tydén
authors.forename: Birgitta
authors.initials: B
authors.lastname: Gullstrand
authors.forename: Eva
authors.initials: E
authors.lastname: Källberg
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ivars
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D040501:Calgranulin A / Q000096:biosynthesis* / Q000276:immunology; D040502:Calgranulin B / Q000096:biosynthesis* / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000276:immunology; D055815:Young Adult
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B