title: Migration inhibitory factor enhances inflammation via CD74 in cartilage end plates with Modic type 1 changes on MRI.
abstract: BACKGROUND
  Type 1 Modic changes are characterized by edema, vascularization, and inflammation, which lead to intervertebral disc degeneration. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine closely related to the inflammatory cytokines detected in degenerative intervertebral disc tissues. However, the existence and role of MIF and its receptor CD74 in intervertebral disc degeneration have not been elucidated.
  
  
  OBJECTIVE
  We asked whether (1) MIF and its receptor CD74 are expressed in cartilage end plates with Type 1 Modic changes, (2) MIF is associated with cartilage end plate degeneration, (3) the MIF antagonist (S, R)-3(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) suppresses MIF-induced inflammatory cytokine release, and (4) inflammatory cytokines are released by cartilage end plate chondrocytes via CD74 by activating the CD74 antibody (CD74Ab).
  
  
  METHODS
  We examined MIF and CD74 expression by human cartilage end plate chondrocytes and tissues with Type 1 Modic changes from eight patients using immunocytofluorescence and immunohistochemistry. MIF production by the chondrocytes was assessed by ELISA and PCR. We compared cytokine release by chondrocytes treated with MIF in the presence or absence of exogenous ISO-1 by ELISA. Cytokine release by chondrocytes after treatment with CD74Ab was determined by ELISA.
  
  
  RESULTS
  MIF was expressed in degenerated human cartilage end plate tissues and chondrocytes. Lipopolysaccharide and tumor necrosis factor α (TNF-α) upregulated MIF expression and increased MIF secretion in chondrocytes in a dose-dependent manner. MIF increased the secretion of IL-6, IL-8, and prostaglandin E2 (PGE2) in a dose-dependent manner. ISO-1 reduced the secretion of IL-6, IL-8, and PGE2. CD74Ab activated CD74 and induced release of inflammatory cytokines.
  
  
  CONCLUSIONS
  Chondrocytes in cartilage end plate with Type 1 Modic changes express MIF and its receptor CD74. MIF might promote the inflammatory response through CD74. MIF-induced cytokine release appears to be suppressed by ISO-1, and CD74Ab could induce cytokine release.
  
  
  CONCLUSIONS
  The MIF/CD74 pathway may represent a crucial target for treating disc degeneration since inhibiting the function of MIF with its antagonist ISO-1 can reduce MIF-induced inflammation and exert potent therapeutic effects.
authors.affiliation: Orthopedic Department, Wuhan General Hospital of Guangzhou Military Area Command, Wuhan, China.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Cun
authors.forename: Bayan G
authors.initials: BG
authors.lastname: Aghdasi
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D002356:Cartilage / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000893:Anti-Inflammatory Agents; D000906:Antibodies; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human