Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo.
Changes in methylation of CpG sites at the interleukin (IL)-4 and interferon (IFN)-gamma promoters are associated with T helper (Th) 2 polarization in vitro. No previous studies have examined whether air pollution or allergen exposure alters methylation of these two genes in vivo. We hypothesized that diesel exhaust particles (DEP) would induce hypermethylation of the IFN-gamma promoter and hypomethylation of IL-4 in CD4+ T cells among mice sensitized to the fungus allergen Aspergillus fumigatus. We also hypothesized that DEP-induced methylation changes would affect immunoglobulin (Ig) E regulation. BALB/c mice were exposed to a 3-week course of inhaled DEP exposure while undergoing intranasal sensitization to A. fumigatus. Purified DNA from splenic CD4+ cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. Sera IgE levels were compared with methylation levels at several CpG sites in the IL-4 and IFN-gamma promoter. Total IgE production was increased following intranasal sensitization A. fumigatus. IgE production was augmented further following combined exposure to A. fumigatus and DEP exposure. Inhaled DEP exposure and intranasal A. fumigatus induced hypermethylation at CpG(-45), CpG(-53), CpG(-205) sites of the IFN-gamma promoter and hypomethylation at CpG(-408) of the IL-4 promoter. Altered methylation of promoters of both genes was correlated significantly with changes in IgE levels. This study is the first to demonstrate that inhaled environmental exposures influence methylation of Th genes in vivo, supporting a new paradigm in asthma pathogenesis.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Jinming
J
Liu
Manisha
M
Ballaney
Umaima
U
Al-alem
Chunli
C
Quan
Ximei
X
Jin
Frederica
F
Perera
Lung-Chi
LC
Chen
Rachel L
RL
Miller
D000485:Allergens; D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology*; D001249:Asthma / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000097:blood*; D019570:Inhalation Exposure; D007371:Interferon-gamma / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D001335:Vehicle Emissions / Q000633:toxicity*
D000485:Allergens; D001335:Vehicle Emissions; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma