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Th2 Cell-Selective Enhancement of Human IL13 Transcription by IL13-1112C>T, a Polymorphism Associated with Allergic Inflammation¹

Lisa Cameron^2,*,, Robin B. Webster^3,*,, Jannine M. Strempel^3,*,, Patricia Kiesler^3,*,, Michael Kabesch^4,*,, Harikrishnan Ramachandran, Lizhi Yu, Debra A. Stern, Penelope E. Graves, I. Carla Lohman, Anne L. Wright^,, Marilyn Halonen^,, Walter T. Klimecki^, and Donata Vercelli^5,*,,¶

^* Functional Genomics Laboratory, Arizona Respiratory Center, and Departments of Pediatrics, Pharmacology, and ^¶ Cell Biology, College of Medicine, University of Arizona, Tucson, AZ 85724

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL66391 (to D.V.) and AI42268 (to A.L.W.), a fellowship from the Canadian Institutes of Health Research (to L.C.), and an Interest Section Award from the American Academy of Allergy, Asthma and Immunology (to L.C.).

² Current address: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

³ R.B.W., J.M.S., and P.K. contributed equally to this work.

⁴ Current address: University Children’s Hospital, Ludwig Maximilian’s University, Munich, Germany.

⁵ Address correspondence and reprint requests to Dr. Donata Vercelli, Arizona Respiratory Center, Arizona Health Sciences Center, Room 2349, 1501 North Campbell Avenue, Tucson, AZ 85724. E-mail address: donata{at}arc.arizona.edu

⁶ Abbreviations used in this paper: SNP, single nucleotide polymorphism; ChIP, chromatin immunoprecipitation; LD, linkage disequilibrium; RLA, relative luciferase activity; YY1, Yin Yang 1; DT, divergence threshold; rh, recombinant human.

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