Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma.
Previous studies have shown that Th2 cytokine genes on mouse chromosome 11 are coordinately regulated by the Th2 locus control region (LCR). To examine the in vivo function of Th2 LCR, we generated CD4-specific Th2 LCR-deficient (cLCR KO) mice using Cre-LoxP recombination. The number of CD4 T cells in the cLCR KO mouse was comparable to that in wild-type mice. The expression of Th2 cytokines was dramatically reduced in in vitro-stimulated naïve CD4 T cells. Deletion of the LCR led to a loss of general histone H3 acetylation and histone H3-K4 methylation, and demethylation of DNA in the Th2 cytokine locus. Upon ovalbumin challenge in the mouse model of allergic asthma, cLCR KO mice exhibited marked reduction in the recruitment of eosinophils and lymphocytes in the bronchoalveolar lavage fluid, serum IgE level, lung airway inflammation, mucus production in the airway walls, and airway hyperresponsiveness. These results directly demonstrate that the Th2 LCR is critically important in the regulation of Th2 cytokine genes, in chromatin remodeling of the Th2 cytokine locus, and in the pathogenesis of allergic asthma.
Koh
Byung Hee
BH
Department of Life Science, Sogang University, Seoul 121-742, Korea.
Hwang
Soo Seok
SS
Kim
Joo Young
JY
Lee
Wonyong
W
Kang
Min-Jong
MJ
Lee
Chun Geun
CG
Park
Jung-Won
JW
Flavell
Richard A
RA
Lee
Gap Ryol
GR
D000818:Animals; D001249:Asthma / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019070:Cell Lineage; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology*; D007113:Immunity, Innate; D019901:Locus Control Region; D051379:Mice; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines