The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/341/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 341-346

Articles

Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis

Marcelo Bozza*, Abhay R. Satoskar*, Guosheng Lin*, Bao Lu{ddagger}, Alison A. Humbles{ddagger}, Craig Gerard{ddagger}, and John R. David*

From the * Department of Immunology and Infectious Diseases, Harvard School of Public Health, and the {ddagger} Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

To study the biologic role of migration inhibitory factor (MIF), a pleiotropic cytokine, we generated a mouse strain lacking MIF by gene targeting in embryonic stem cells. Analysis of the role of MIF during sepsis showed that MIF–/– mice were resistant to the lethal effects of high dose bacterial lipopolysaccharide (LPS), or Staphylococcus aureus enterotoxin B (SEB) with D-galactosamine and had lower plasma levels of tumor necrosis factor {alpha} (TNF-{alpha}) than did wild-type mice, but normal levels of interleukin (IL)-6 and IL-10. When stimulated with LPS and interferon {gamma}, macrophages from MIF–/– mice showed diminished production of TNF-{alpha}, normal IL-6 and IL-12, and increased production of nitric oxide. MIF–/– animals cleared gram-negative bacteria Pseudomonas aeruginosa instilled into the trachea better than did wild-type mice and had diminished neutrophil accumulation in their bronchoalveolar fluid compared to the wild-type mice. Thioglycollate elicited peritoneal exudates in uninfected MIF–/– mice, but showed normal neutrophil accumulation. Finally, the findings of enhanced resistance to P. aeruginosa and resistance to endotoxin-induced lethal shock suggest that the counteraction or neutralization of MIF may serve as an adjunct therapy in sepsis.

Key Words: migration inhibitory factor • gene-deficient mice • sepsis • lipopolysaccharide • Pseudomonas aeruginosa

Address correspondence to John R. David, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. Phone: 617-432-1201; Fax: 617-738-4914; E-mail: jdavid{at}hsph.harvard.edu

Marcelo Bozza's present address is Laboratorio de Farmacologia Aplicada, Far Manguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.

1 Abbreviations used in this paper: BAL, bronchoalveolar lavage; ES, embryonic stem; MIF, migration inhibitory factor; NO, nitric oxide; SEB, Staphylococcus aureus enterotoxin B.


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