title: Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation.
abstract: 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.
authors.affiliation: Functional Genomics Laboratory, and Arizona Respiratory Center, College of Medicine, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cameron
authors.forename: Robin B
authors.initials: RB
authors.lastname: Webster
authors.forename: Jannine M
authors.initials: JM
authors.lastname: Strempel
authors.forename: Patricia
authors.initials: P
authors.lastname: Kiesler
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Harikrishnan
authors.initials: H
authors.lastname: Ramachandran
authors.forename: Lizhi
authors.initials: L
authors.lastname: Yu
authors.forename: Debra A
authors.initials: DA
authors.lastname: Stern
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Graves
authors.forename: I Carla
authors.initials: IC
authors.lastname: Lohman
authors.forename: Anne L
authors.initials: AL
authors.lastname: Wright
authors.forename: Marilyn
authors.initials: M
authors.lastname: Halonen
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
authors.forename: Donata
authors.initials: D
authors.lastname: Vercelli
mesh_terms: 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
chemical_list: D018793:Interleukin-13