title: CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis.
abstract: OBJECTIVE
  CD14+,CD16+ monocytes, identified as a minor population of monocytes in human peripheral blood (PB), have been implicated in several inflammatory diseases. We undertook this study to investigate the relevance of this phenotype to joint inflammation in rheumatoid arthritis (RA).
  
  
  METHODS
  The expression of CD14, CD16, CC chemokine receptor 1 (CCR1), CCR5, and intercellular adhesion molecule 1 (ICAM-1) on monocytes was measured by flow cytometric analysis. Concentrations of the cytokines known to induce CD16 (including transforming growth factor beta1 [TGFbeta1], macrophage colony-stimulating factor [M-CSF], and interleukin-10 [IL-10]) and concentrations of the soluble form of CD14 (sCD14) in plasma and synovial fluid (SF) samples were measured by enzyme-linked immunosorbent assay. The induction of CD16 on RA blood monocytes cultured for 18 hours with 1 or with all 3 cytokines was determined.
  
  
  RESULTS
  The mean +/- SD frequency of CD14+,CD16+ blood monocytes was significantly increased in RA patients (11.7 +/- 5.6%; n = 105) compared with healthy controls (9.5 +/- 2.2%; n = 15) (P < 0.01), and the patient group with an increased frequency of CD16+ monocytes (> or =13.9%) had active disease, as defined by increased counts of tender and swollen joints, levels of acute-phase reactants, and titers of rheumatoid factor. The response to drug therapy correlated with changes in the frequency of this phenotype. The expression of CD16 on SF monocytes from RA patients was markedly elevated compared with the expression on PB monocytes. CD16 expression on RA blood monocytes was augmented in vitro by IL-10, M-CSF, and TGFbeta1. Plasma concentrations of these cytokines and of sCD14 were significantly higher in RA patients with high CD16+ monocyte frequencies than in those with low CD16+ monocyte frequencies or in healthy controls. CD14+,CD16+ monocytes expressed higher levels of CCR1, CCR5, and ICAM-1 than did regular CD14++,CD16- monocytes, particularly in active RA.
  
  
  CONCLUSIONS
  These results indicate that the maturation of blood monocytes into tissue-infiltrative CD16+ cells before entry into the joint, induced by cytokine spillover from the inflamed joint, may contribute to the persistent joint inflammation of RA.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Norikuni
authors.initials: N
authors.lastname: Kawanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamura
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Aita
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Morita
authors.forename: Akira
authors.initials: A
authors.lastname: Okamoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawashima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Iwahashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Ueno
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Ohmoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis; D016753:Interleukin-10 / Q000097:blood / Q000494:pharmacology; D007596:Joints / Q000276:immunology; D007958:Leukocyte Count; D018950:Lipopolysaccharide Receptors / Q000032:analysis* / Q000097:blood; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000032:analysis / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000032:analysis / Q000096:biosynthesis; D017452:Receptors, IgG / Q000032:analysis*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000097:blood / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: C515300:CCR1 protein, human; D018950:Lipopolysaccharide Receptors; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D017452:Receptors, IgG; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor