title: Macrophage migration inhibitory factor down-regulates the RANKL-RANK signaling pathway by activating Lyn tyrosine kinase in mouse models.
abstract: OBJECTIVE
  Macrophage migration inhibitory factor (MIF) is an important modulator of innate and adaptive immunity as well as local inflammatory responses. We previously reported that MIF down-regulated osteoclastogenesis through a mechanism that requires CD74. The aim of the current study was to examine whether MIF modulates osteoclastogenesis through Lyn phosphorylation, and whether down-regulation of RANKL-mediated signaling requires the association of CD74, CD44, and Lyn.
  
  
  METHODS
  CD74-knockout (CD74-KO), CD44-KO, and Lyn-KO mouse models were used to investigate whether Lyn requires these receptors and coreceptors. The effects of MIF on osteoclastogenesis were assessed using Western blot analysis, small interfering RNA (siRNA)-targeted down-regulation of Lyn, Lyn-KO mice, and real-time imaging of Lyn molecules to surface proteins.
  
  
  RESULTS
  MIF treatment induced Lyn expression, and MIF down-regulated RANKL-induced activator protein 1 (AP-1) and the Syk/phospholipase Cγ cascade during osteoclastogenesis through activated Lyn tyrosine kinase. The results of immunoprecipitation studies revealed that MIF receptors associated with Lyn in response to MIF treatment. Studies using Lyn-specific siRNA and Lyn-KO mice confirmed our findings.
  
  
  CONCLUSIONS
  Our findings indicate that the tyrosine kinase Lyn is activated when MIF binds to its receptor CD74 and its coreceptor CD44 and, in turn, down-regulates the RANKL-mediated signaling cascade by suppressing NF-ATc1 protein expression through down-regulation of AP-1 and calcium signaling components.
authors.affiliation: University of Connecticut Health Center, Farmington.
authors.forename: Se Hwan
authors.initials: SH
authors.lastname: Mun
authors.forename: Dongmyung
authors.initials: D
authors.lastname: Oh
authors.forename: Sun-Kyeong
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D019746:Intramolecular Oxidoreductases / Q000494:pharmacology*; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse