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* Division of Allergy and Immunology,
Graduate Program of Molecular and Developmental Biology, and
Physician Scientist Training Program, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229
Allergic airway inflammation is characterized by marked in situ changes in gene and protein expression, yet the role of microRNAs (miRNAs), a new family of key mRNA regulatory molecules, in this process has not yet been reported. Using a highly sensitive microarray-based approach, we identified 21 miRNAs with differential expression between doxycycline-induced lung-specific IL-13 transgenic mice (with allergic airway inflammation) and control mice. In particular, we observed overexpression of miR-21 and underexpression of miR-1 in the induced IL-13 transgenic mice compared with control mice. These findings were validated in two independent models of allergen-induced allergic airway inflammation and in IL-4 lung transgenic mice. Although IL-13-induced miR-21 expression was IL-13R
1 dependent, allergen-induced miR-21 expression was mediated mainly independent of IL-13R1 and STAT6. Notably, predictive algorithms identified potential direct miR-21 targets among IL-13-regulated lung transcripts, such as IL-12p35 mRNA, which was decreased in IL-13 transgenic mice. Introduction of pre-miR-21 dose dependently inhibited cellular expression of a reporter vector harboring the 3'-untranslated region of IL-12p35. Moreover, mutating miR-21 binding sites in IL-12p35 3'-untranslated region abrogated miR-21-mediated repression. In summary, we have identified a miRNA signature in allergic airway inflammation, which includes miR-21 that modulates IL-12, a molecule germane to Th cell polarization.
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 P01 HL076383 (to M.E.R.) and R01 AI057803 (to M.E.R.), and the Organogenesis Training Grant (National Institutes of Health T32 HD046387 supporting T.X.L.). This work was also supported by Medical Scientist Training Program training grant (T32 GM063483 supporting T.X.L.) from the National Institute of General Medical Sciences.
2 Address correspondence and reprint requests to Dr. Marc E. Rothenberg, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail address: Rothenberg{at}cchmc.org
3 Abbreviations used in this paper: mi, micro; HPRT, hypoxanthine phosphoribosyltransferase; LNA, locked nucleic acid; NFIB, nuclear factor IB; qRT-PCR, quantitative RT-PCR; UTR, untranslated region.
4 The online version of this article contains supplemental material.
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