Identification of novel susceptibility genes in ozone-induced inflammation in mice.
Ozone (O(3)) remains a prevalent air pollutant and public health concern. Inf2 is a significant quantitative trait locus on murine chromosome 17 that contributes to susceptibility to O(3)-induced infiltration of polymorphonuclear leukocytes (PMNs) into the lung, but the mechanisms of susceptibility remain unclear. The study objectives were to confirm and restrict Inf2, and to identify and test novel candidate susceptibility gene(s). Congenic strains of mice that contained overlapping regions of Inf2 and their controls, and mice deficient in either major histocompatibility complex (MHC) class II genes or the Tnf cluster, were exposed to air or O(3). Lung inflammation and gene expression were assessed. Inf2 was restricted from 16.42 Mbp to 0.96 Mbp, and bioinformatic analysis identified MHC class II, the Tnf cluster and other genes in this region that contain potentially informative single nucleotide polymorphisms between the susceptible and resistant mice. Furthermore, O(3)-induced inflammation was significantly reduced in mice deficient in MHC class II genes or the Tnf cluster genes, compared with wild-type controls. Gene expression differences were also observed in MHC class II and Tnf cluster genes. This integrative genetic analysis of Inf2 led to identification of novel O(3) susceptibility genes that may provide important, new therapeutic targets in susceptible individuals.
Bauer
A K
AK
Dept of Pathobiology and Diagnostic Investigation Center for Integrative Toxicology B43 Food Safety and Toxicology Bldg, Michigan State University, East Lansing, MI 48824, USA. akbauer@msu.edu
Travis
E L
EL
Malhotra
S S
SS
Rondini
E A
EA
Walker
C
C
Cho
H-Y
HY
Trivedi
S
S
Gladwell
W
W
Reddy
S
S
Kleeberger
S R
SR
D000818:Animals; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007249:Inflammation; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D020297:Mice, Congenic; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D005810:Multigene Family; D009504:Neutrophils / Q000166:cytology; D010126:Ozone / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone