Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation.
IL-13 is a central mediator of allergic inflammation. The single nucleotide polymorphism IL13-1112C>T (rs1800925) is associated with allergic phenotypes in ethnically distinct populations, but the underlying mechanism(s) remain unknown. Using in vivo, in vitro, and in silico analysis, we show that the IL13-1112T allele enhanced IL13 promoter activity in primary human and murine CD4(+) Th2 lymphocytes. Increased expression of IL13-1112T in Th2 cells was associated with the creation of a Yin-Yang 1 binding site that overlapped a STAT motif involved in negative regulation of IL13 expression and attenuated STAT6-mediated transcriptional repression. Because IL-13 secretion was increased in IL13-1112TT homozygotes, we propose that increased expression of IL13-1112T in vivo may underlie its association with susceptibility to allergic inflammation. Interestingly, IL13-1112T had opposite transcriptional effects in nonpolarized CD4(+) T cells, paralleled by distinct patterns of DNA-protein interactions at the IL13 promoter. Our findings suggest the nuclear milieu dictates the functional outcome of genetic variation.
Cameron
Lisa
L
Functional Genomics Laboratory, and Arizona Respiratory Center, College of Medicine, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
Webster
Robin B
RB
Strempel
Jannine M
JM
Kiesler
Patricia
P
Kabesch
Michael
M
Ramachandran
Harikrishnan
H
Yu
Lizhi
L
Stern
Debra A
DA
Graves
Penelope E
PE
Lohman
I Carla
IC
Wright
Anne L
AL
Halonen
Marilyn
M
Klimecki
Walter T
WT
Vercelli
Donata
D
D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D006967:Hypersensitivity / Q000473:pathology*; D007249:Inflammation / Q000235:genetics*; D018793:Interleukin-13 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018418:Th2 Cells / Q000502:physiology*; D014158:Transcription, Genetic
D018793:Interleukin-13