title: Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice.
abstract: Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (ε2, ε3, and ε4) reflecting single amino acid substitutions at amino acids 112 and 158. The objective of this study was to assess whether the human apoE alleles modify airway responses to repeated nasal HDM challenges. Mice expressing the human apoE ε2 (huApoE2), ε3 (huApoE3), or ε4 (huApoE4) alleles received nasal HDM challenges, and airway responses were compared with mice expressing the endogenous murine apoE gene (muApoE). huApoE3 mice displayed significant reductions in AHR, mucous cell metaplasia, and airway inflammation compared with muApoE mice. The attenuated severity of airway inflammation in huApoE3 mice was associated with reductions in lung mRNA levels of Th2 and Th17 cytokines, as well as chemokines (CCL7, CCL11, CCL24). huApoE4 mice had an intermediate phenotype, with attenuated AHR and IgE production, compared with muApoE mice, whereas airway inflammation and mucous cell metaplasia were not reduced. In contrast, HDM-induced airway responses were not modified in mice expressing the huApoE2 allele. We conclude that the polymorphic huApoE alleles differentially modulate HDM-induced airway disease, which can be stratified, in rank order of increasing disease severity, ε3 < ε4 < ε2. These results raise the possibility that the polymorphic apoE alleles may modify disease severity in human asthma.
authors: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg. 10, Rm. 6D03, MSC 1590, Bethesda, MD 20892-1590, USA.
authors: Xianglan
authors: X
authors: Yao
authors: Cuilian
authors: C
authors: Dai
authors: Karin
authors: K
authors: Fredriksson
authors: Jonathan
authors: J
authors: Lam
authors: Meixia
authors: M
authors: Gao
authors: Karen J
authors: KJ
authors: Keeran
authors: Gayle Zywicke
authors: GZ
authors: Nugent
authors: Xuan
authors: X
authors: Qu
authors: Zu-Xi
authors: ZX
authors: Yu
authors: Neal
authors: N
authors: Jeffries
authors: JingPing
authors: J
authors: Lin
authors: Maryann
authors: M
authors: Kaler
authors: Robert
authors: R
authors: Shamburek
authors: Rene
authors: R
authors: Costello
authors: Gyorgy
authors: G
authors: Csako
authors: Morten
authors: M
authors: Dahl
authors: Børge G
authors: BG
authors: Nordestgaard
authors: Alan T
authors: AT
authors: Remaley
authors: Stewart J
authors: SJ
authors: Levine
mesh_terms: D000483:Alleles; D000485:Allergens / Q000276:immunology*; D019943:Amino Acid Substitution; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D054413:Chemokine CCL11 / Q000096:biosynthesis; D054423:Chemokine CCL24 / Q000096:biosynthesis; D054410:Chemokine CCL7 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D007073:Immunoglobulin E / Q000096:biosynthesis; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D001057:Apolipoproteins E; C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; C515451:Ccl7 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D054410:Chemokine CCL7; D016207:Cytokines; D012333:RNA, Messenger; D007073:Immunoglobulin E