Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation.
Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF(-/-) mice occurs regardless of high concentrations of IL-4 in the lung and OVA-specific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF(-/-) mice compared to WT, but were reduced in the spleen of MIF(-/-), thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4(+) cells with anti-CD3 antibody demonstrated that MIF(-/-) cells produced increased amounts of IFN-gamma and IL-4 compared to WT CD4(+) cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma.
Magalhães
Elizabeth S
ES
Departamento de Imunologia, Instituto de Microbiologia, UFRJ, Rio de Janeiro, Brazil.
Mourao-Sa
Diego S
DS
Vieira-de-Abreu
Adriana
A
Figueiredo
Rodrigo T
RT
Pires
Ana L
AL
Farias-Filho
Francisco A
FA
Fonseca
Bruna P F
BP
Viola
João P B
JP
Metz
Christine
C
Martins
Marco A
MA
Castro-Faria-Neto
Hugo C
HC
Bozza
Patrícia T
PT
Bozza
Marcelo T
MT
D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D007106:Immune Sera / Q000008:administration & dosage; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
D000485:Allergens; D007106:Immune Sera; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse