The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD

PLoS One. 2016 Jan 11;11(1):e0146102. doi: 10.1371/journal.pone.0146102. eCollection 2016.


Introduction: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however.

Methods: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays.

Results: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR.

Conclusion: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use*
  • Adult
  • Aged
  • Animals
  • Bronchoalveolar Lavage Fluid
  • Cell Count
  • Cytokines / metabolism
  • Dexamethasone / pharmacology
  • Disease Models, Animal
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Isoxazoles / therapeutic use*
  • Lung / pathology
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Ozone
  • Pneumonia / complications*
  • Pneumonia / genetics
  • Pneumonia / pathology
  • Pneumonia / physiopathology
  • Pulmonary Disease, Chronic Obstructive / complications*
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Respiratory Function Tests
  • Respiratory Hypersensitivity / complications*
  • Respiratory Hypersensitivity / drug therapy
  • Respiratory Hypersensitivity / genetics
  • Respiratory Hypersensitivity / physiopathology
  • Smoking / adverse effects
  • Sputum / drug effects
  • Sputum / metabolism


  • 3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester
  • Adrenal Cortex Hormones
  • Cytokines
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoxazoles
  • Macrophage Migration-Inhibitory Factors
  • RNA, Messenger
  • Ozone
  • Dexamethasone