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Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis
1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Abstract:
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.
Insights
Mice lacking migration inhibitory factor (MIF) showed resistance to sepsis and endotoxin shock. Neutralizing MIF could be a potential adjunctive therapy for sepsis treatment.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Migration inhibitory factor (MIF) is a pleiotropic cytokine with significant biological roles.
- Understanding MIF's function is crucial for developing targeted therapies for inflammatory diseases.
Purpose of the Study:
- To investigate the biological role of MIF by generating and analyzing a mouse strain lacking MIF (MIF-/-).
- To assess the impact of MIF deficiency on sepsis, immune responses, and bacterial clearance.
Main Methods:
- Gene targeting in embryonic stem cells was used to create MIF-/- mice.
- Mice were subjected to challenges with lipopolysaccharide (LPS), Staphylococcus aureus enterotoxin B (SEB), and Pseudomonas aeruginosa.
- Immune responses, including cytokine production (TNF-alpha, IL-6, IL-10, IL-12) and neutrophil accumulation, were analyzed.
Main Results:
- MIF-/- mice exhibited resistance to lethal effects of LPS and SEB-induced shock, with lower plasma TNF-alpha levels.
- Macrophages from MIF-/- mice showed diminished TNF-alpha production but normal IL-6, IL-12, and increased nitric oxide production upon stimulation.
- MIF-/- mice demonstrated enhanced clearance of Pseudomonas aeruginosa and reduced neutrophil accumulation in the lungs.
Conclusions:
- MIF plays a critical role in mediating lethal shock and inflammatory responses during sepsis.
- The absence of MIF confers resistance to endotoxin shock and improves bacterial clearance.
- Counteracting or neutralizing MIF may represent a promising adjunctive therapeutic strategy for sepsis.