title: Macrophage migration inhibitory factor enzymatic activity, lung inflammation, and cystic fibrosis.
abstract: BACKGROUND
  Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator with unique tautomerase enzymatic activity; the precise function has not been clearly defined. We previously demonstrated that individual patients with cystic fibrosis (CF) who are genetically predisposed to be high MIF producers develop accelerated end-organ injury.
  
  
  OBJECTIVE
  To characterize the effects of the MIF-CATT polymorphism in patients with CF ex vivo. To investigate the role of MIF's tautomerase activity in a murine model of Pseudomonas aeruginosa infection.
  
  
  METHODS
  MIF and tumor necrosis factor (TNF)-α protein levels were assessed in plasma or peripheral blood mononuclear cell (PBMC) supernatants by ELISA. A murine pulmonary model of chronic Pseudomonas infection was used in MIF wild-type mice (mif(+/+)) and in tautomerase-null, MIF gene knockin mice (mif (P1G/P1G)).
  
  
  RESULTS
  MIF protein was measured in plasma and PBMCs from 5- and 6-CATT patients with CF; LPS-induced TNF-α production from PBMCs was also assessed. The effect of a specific inhibitor of MIF-tautomerase activity, ISO-1, was investigated in PBMCs. In the murine infection model, total weight loss, differential cell counts, bacterial load, and intraacinar airspace/tissue volume were measured. MIF and TNF-α levels were increased in 6-CATT compared with 5-CATT patients with CF. LPS-induced TNF-α production from PBMCs was attenuated in the presence of ISO-1. In a murine model of Pseudomonas infection, significantly less pulmonary inflammation and bacterial load was observed in mif(P1G/P1G) compared with mif(+/+) mice.
  
  
  CONCLUSIONS
  MIF-tautomerase activity may provide a novel therapeutic target in patients with chronic inflammatory diseases such as CF, particularly those patients who are genetically predisposed to produce increased levels of this cytokine.
authors.affiliation: School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: Huzaifa
authors.initials: H
authors.lastname: Adamali
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Armstrong
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: McLaughlin
authors.forename: Gordon
authors.initials: G
authors.lastname: Cooke
authors.forename: Edward
authors.initials: E
authors.lastname: McKone
authors.forename: Christine M
authors.initials: CM
authors.lastname: Costello
authors.forename: Charles G
authors.initials: CG
authors.lastname: Gallagher
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: John A
authors.initials: JA
authors.lastname: Baugh
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bucala
authors.forename: Paul
authors.initials: P
authors.lastname: McLoughlin
authors.forename: Seamas C
authors.initials: SC
authors.lastname: Donnelly
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D003550:Cystic Fibrosis / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000097:blood / Q000201:enzymology / Q000209:etiology; D011110:Polymorphism, Genetic; D011552:Pseudomonas Infections / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D012141:Respiratory Tract Infections / Q000276:immunology; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha