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Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.

ABSTRACT: TGF? activation and signaling have been extensively studied in experimental models of allergen-induced asthma as potential therapeutic targets during chronic or acute phases of the disease. Outcomes of experimental manipulation of TGF? activity have been variable, in part due to use of different model systems. Using an ovalbumin (OVA)-induced mouse model of asthma, we here show that innate variation within TGF?1 genetic modifier loci, Tgfbm2 and Tgfbm3, alters disease susceptibility. Specifically, Tgfbm2(129) and Tgfbm3(C57) synergize to reverse accentuated airway hyperresponsiveness (AHR) caused by low TGF?1 levels in Tgfb1(+/-) mice of the NIH/OlaHsd strain. Moreover, epistatic interaction between Tgfbm2(129) and Tgfbm3(C57) uncouples the inflammatory response to ovalbumin from those of airway remodeling and airway hyperresponsiveness, illustrating independent genetic control of these responses. We conclude that differential inheritance of genetic variants of Tgfbm genes alters biological responses to reduced TGF?1 signaling in an experimental asthma model. TGF? antagonists for treatment of lung diseases might therefore give diverse outcomes, dependent on genetic variation.

SUBMITTER: Freimuth J

PROVIDER: S-EPMC3497801 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.

Freimuth Julia J Clermont Frederic F FF Huang Xiaozhu X DeSapio Angela A Tokuyasu Taku A TA Sheppard Dean D Akhurst Rosemary J RJ

Proceedings of the National Academy of Sciences of the United States of America 20121011 44

TGFβ activation and signaling have been extensively studied in experimental models of allergen-induced asthma as potential therapeutic targets during chronic or acute phases of the disease. Outcomes of experimental manipulation of TGFβ activity have been variable, in part due to use of different model systems. Using an ovalbumin (OVA)-induced mouse model of asthma, we here show that innate variation within TGFβ1 genetic modifier loci, Tgfbm2 and Tgfbm3, alters disease susceptibility. Specificall ...[more]

PMID: 23064636

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Dataset Information

Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.

Publications

Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.

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