title: Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity.
abstract: BACKGROUND
  Progranulin (PGRN) is the precursor of granulin (GRN), a soluble cofactor for toll-like receptor 9 (TLR9) signaling evoked by oligonucleotide (CpG)-DNA. Because TLR9 signaling plays an important role in systemic lupus erythematosus (SLE), we investigated whether PGRN is involved in the pathogenesis of SLE.
  
  
  METHODS
  We measured concentrations of serum PGRN and interleukin-6 (IL-6) with enzyme-linked immunosorbent assay (ELISA) in patients with SLE (n = 68) and in healthy controls (n = 60). We assessed the correlation between the serum PGRN levels and established disease-activity indexes. The sera from the patients with high PGRN titers (>80 ng/ml) at the initial evaluation were reevaluated after the disease was ameliorated by treatment. We also measured the IL-6 concentration secreted by peripheral blood mononuclear cells (PBMCs) incubated with (a) oligonucleotide (CpG-B) in the presence or absence of recombinant human PGRN (rhPGRN); and (b) lupus sera in the presence or absence of a neutralizing anti-PGRN antibody.
  
  
  RESULTS
  Serum PGRN levels were significantly higher in SLE patients than healthy controls. Their levels were significantly associated with activity of clinical symptoms. They also significantly correlated with values of clinical parameters, including the SLE Disease Activity Index and anti-double-stranded DNA antibody titers, and inversely with CH50, C3, and C4 levels. Moreover, serum PGRN levels significantly decreased after successful treatment of SLE. The rhPGRN significantly upregulated the production of IL-6 by PBMCs stimulated with CpG-B. Patients' sera stimulated production of IL-6 from PBMCs, which was significantly impaired by neutralization of PGRN. The serum PGRN levels significantly correlated with the serum IL-6 levels.
  
  
  CONCLUSIONS
  Serum PGRN could be a useful biomarker for disease activity of SLE. PGRN may be involved in the pathogenesis of SLE partly by enhancing the TLR9 signaling.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mitoma
authors.forename: Chikako
authors.initials: C
authors.lastname: Kiyohara
authors.forename: Naoyasu
authors.initials: N
authors.lastname: Ueda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ayano
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Ohta
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yojirou
authors.initials: Y
authors.lastname: Arinobu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Takahiko
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015415:Biomarkers / Q000097:blood*; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D000077153:Progranulins; D011994:Recombinant Proteins / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D015415:Biomarkers; D003176:Complement C3; D003181:Complement C4; C513201:CpG-B 2006; C492314:GRN protein, human; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D000077153:Progranulins; D011994:Recombinant Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D003165:Complement System Proteins