Expression of survivin in lung eosinophils is associated with pathology in a mouse model of allergic asthma.
Humans vary markedly in their propensity to develop asthma, despite often being exposed to similar environmental stimuli. Similarly, mouse strains vary in susceptibility to airways pathology in experimental asthma. Sensitization and aerosol challenge with ovalbumin (OVA) induces eosinophil accumulation, mucus production and airways obstruction in BALB/c and C57BL/6 mice. In contrast, CBA/Ca mice show relatively little pathology. Allergen-induced production of IL-4, IL-5, IL-10 and IFN-gamma was detected in all three strains, with BALB/c mice generating the highest levels of IL-4, IL-5 and IL-10. Microarray analysis was used to identify genes differentially regulated in lung tissue after OVA challenge. Differentially regulated genes in the lungs of the asthma-susceptible C57BL/6 and BALB/c strains numbered 242 and 145, respectively, whereas only 42 genes were differentially expressed in the resistant CBA/Ca strain. In C57BL/6 mice, transcripts were enriched for adhesion molecules and this was associated with high levels of eosinophil recruitment. Differentially regulated genes in the lungs of only the asthma-susceptible strains numbered 64 and several of these have not previously been associated with asthma. Many of the genes differentially regulated in the susceptible strains were enzymes involved in inflammation. Using network analysis, mRNA for the anti-apoptotic protein survivin was found to be up-regulated in the lungs following allergen challenge. Survivin mRNA and protein were also expressed at high levels in eosinophils recovered by bronchoalveolar lavage from BALB/c and C57BL/6 mice. We propose that rapid apoptosis of lung eosinophils due to low expression of survivin contributes to the limitation of pathology in CBA/Ca mice.
Tumes
Damon J
DJ
School of Molecular and Biomedical Science, University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia.
Connolly
Ashley
A
Dent
Lindsay A
LA
D000402:Airway Obstruction; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007114:Immunization; D051034:Inhibitor of Apoptosis Proteins; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009093:Mucus; D010047:Ovalbumin / Q000008:administration & dosage; D012097:Repressor Proteins; D013045:Species Specificity; D000077022:Survivin
D000485:Allergens; C117749:Birc5 protein, mouse; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D010047:Ovalbumin