Macrophage migration inhibitory factor enzymatic activity, lung inflammation, and cystic fibrosis

Am J Respir Crit Care Med. 2012 Jul 15;186(2):162-9. doi: 10.1164/rccm.201110-1864OC. Epub 2012 May 16.

Abstract

Rationale: 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.

Objectives: 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)).

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Animals
  • Cystic Fibrosis / blood
  • Cystic Fibrosis / enzymology*
  • Cystic Fibrosis / etiology
  • Cystic Fibrosis / genetics
  • Female
  • Gene Knock-In Techniques
  • Humans
  • Macrophage Migration-Inhibitory Factors / blood
  • Macrophage Migration-Inhibitory Factors / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pneumonia / blood
  • Pneumonia / enzymology
  • Pneumonia / etiology
  • Polymorphism, Genetic
  • Pseudomonas Infections / immunology
  • Real-Time Polymerase Chain Reaction
  • Repetitive Sequences, Nucleic Acid / genetics
  • Respiratory Tract Infections / immunology
  • Retrospective Studies
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Macrophage Migration-Inhibitory Factors
  • Tumor Necrosis Factor-alpha