title: Acute CD4+ T lymphocyte-dependent interleukin-1-driven arthritis selectively requires interleukin-2 and interleukin-4, joint macrophages, granulocyte-macrophage colony-stimulating factor, interleukin-6, and leukemia inhibitory factor.
abstract: OBJECTIVE
  To further investigate the effects of interleukin-1 (IL-1) in immune-mediated joint inflammation, we examined the role of IL-2, Th1 interferon-gamma (IFNgamma), and Th2 (IL-4) cytokines, joint macrophages, and macrophage-derived cytokines (IL-12 p40, IL-6, leukemia inhibitory factor [LIF], oncostatin M [OSM], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in a CD4+ T lymphocyte-dependent model of acute arthritis.
  
  
  METHODS
  Methylated bovine serum albumin (mBSA)/IL-1-induced arthritis was elicited in wild-type, gene-knockout, and monoclonal antibody-treated mice. Synovial lining macrophages were selectively depleted by intraarticular injection of clodronate liposomes prior to disease induction. The severity of arthritis was assessed histologically.
  
  
  RESULTS
  Mice deficient in IL-2 were almost completely protected from arthritis, and neutralization of IL-4 reduced the severity of disease. In contrast, arthritis severity and resolution appeared to be independent of IFNgamma. Synovial lining macrophage depletion markedly reduced arthritis severity. IL-6 or LIF deficiency was only modestly protective, although as previously reported, GM-CSF deficiency conferred profound disease resistance. IL-12 p40-deficient mice (which lack IL-12 and IL-23) and OSM receptor-deficient mice were susceptible to mBSA/IL-1-induced arthritis.
  
  
  CONCLUSIONS
  Acute mBSA/IL-1-induced arthritis is dependent on IL-2 and IL-4, but not IFNgamma. In vivo, the Th1/Th2 paradigm may be distorted by the presence of macrophage-derived cytokines such as IL-1. Synovial lining macrophages are essential in mBSA/IL-1-induced arthritis. However, the requirement for macrophage-derived cytokines is selective; that is, IL-6, LIF, and especially GM-CSF are necessary, but IL-12, IL-23, and OSM are dispensable. IL-1 may therefore influence both adaptive and innate immune mechanisms in acute inflammatory arthritis.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.forename: Peter K K
authors.initials: PK
authors.lastname: Wong
authors.forename: Ian K
authors.initials: IK
authors.lastname: Campbell
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Ian P
authors.initials: IP
authors.lastname: Wicks
mesh_terms: D000208:Acute Disease; D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics* / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007596:Joints / Q000276:immunology / Q000473:pathology; D053605:Leukemia Inhibitory Factor; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology; D053677:Receptors, Oncostatin M; D012710:Serum Albumin, Bovine; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D053762:Interleukin-12 Subunit p40; D007376:Interleukin-2; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D021122:Protein Subunits; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D001613:beta 2-Microglobulin; C029180:methylated bovine serum albumin; D018664:Interleukin-12; D015847:Interleukin-4; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor