Macrophage Migration Inhibitory Factor Enzymatic Activity, Lung Inflammation, and Cystic Fibrosis

作者：Adamali Huzaifa; Armstrong Michelle E; McLaughlin Anne Marie; Cooke Gordon; McKone Edward; Costello Christine M; Gallagher Charles G; Leng Lin; Baugh John A; Fingerle Rowson Guenter; Bucala Richard J; McLoughlin Paul; Donnelly Seamas C^*

来源：American Journal of Respiratory and Critical Care Medicine, 2012, 186(2): 162-169.

DOI：10.1164/rccm.201110-1864OC

• cytokines
• macrophage migration inhibitory factor (MIF)
• infection
• inflammation

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. %26lt;br%26gt;Objectives: To characterize the effects of the MIF-CATT polymorphism in patients with CF ex vivo. To investigate the role of MIF%26apos;s tautomerase activity in a murine model of Pseudomonas aeruginosa infection. %26lt;br%26gt;Methods: MIF and tumor necrosis factor (TNF)-alpha 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)). %26lt;br%26gt;Measurements and Main Results: M IF protein was measured in plasma and PBMCs from 5- and 6-CATT patients with CF; LPS-induced TNF-alpha 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-alpha levels were increased in 6-CATT compared with 5-CATT patients with CF. LPS-induced TNF-alpha 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. %26lt;br%26gt;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.

• 出版日期2012-7-15