Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis.
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.
Bozza
M
M
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Satoskar
A R
AR
Lin
G
G
Lu
B
B
Humbles
A A
AA
Gerard
C
C
David
J R
JR
D000818:Animals; D004768:Enterotoxins / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000628:therapy; D013864:Thioglycolates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004768:Enterotoxins; D007378:Interleukins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma