title: Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages. Implications for the control of joint inflammation in gout.
abstract: OBJECTIVE
  We have hypothesized that the process of monocyte to macrophage differentiation may alter the inflammatory response of mononuclear phagocytes to the uptake of monosodium urate monohydrate (MSU) crystals.
  
  
  METHODS
  Eight mouse monocyte/macrophage cell lines were arranged in increasing order of differentiation, as judged by expression of the macrophage markers F4/80 and BM 8 and by phagocytic capacity. Secretion of tumor necrosis factor alpha (TNFalpha) in response to MSU was measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  The panel of monocyte/macrophage cell lines revealed a close linkage between the state of differentiation and the capacity of the cells to ingest MSU crystals. TNFalpha production, however, was not linked to phagocytic ability. Peak TNFalpha levels were synthesized by cells at an intermediate state of differentiation (3.2-14.1 ng/ml), whereas mature macrophages, which efficiently phagocytosed crystals, did not secrete TNFalpha. Mature cell lines produced TNFalpha when stimulated with zymosan (5.9-6.2 ng/ml), but this was abolished by coincubation with MSU crystals. Suppression of the zymosan response was not due to apoptosis or steric hindrance by MSU crystals. Culture supernatants from mature macrophages did not stimulate endothelial cell activation, in contrast to MSU-treated cells at an earlier stage of differentiation, which stimulated intercellular adhesion molecule 1 expression on sEND endothelioma cells through the release of TNFalpha (inhibited 80.6% by anti-TNFa).
  
  
  CONCLUSIONS
  We demonstrated that phagocytosis and TNFalpha production are distinct events in the response of mononuclear phagocytes to urate crystals, and these events can be distinguished at the level of macrophage differentiation. The noninflammatory removal of urate crystals by mature macrophages defines a new pathway that may be important in controlling the development of acute gout in patients with hyperuricemia.
authors.affiliation: BHF Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Yagnik
authors.forename: P
authors.initials: P
authors.lastname: Hillyer
authors.forename: D
authors.initials: D
authors.lastname: Marshall
authors.forename: C D
authors.initials: CD
authors.lastname: Smythe
authors.forename: T
authors.initials: T
authors.lastname: Krausz
authors.forename: D O
authors.initials: DO
authors.lastname: Haskard
authors.forename: R C
authors.initials: RC
authors.lastname: Landis
mesh_terms: D000818:Animals; D015210:Arthritis, Gouty; D002454:Cell Differentiation; D002457:Cell Extracts / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D010587:Phagocytosis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014527:Uric Acid / Q000276:immunology*
chemical_list: D002457:Cell Extracts; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid