MicroRNA-21 Is Up-Regulated in Allergic Airway Inflammation and Regulates IL-12p35 Expression

被引:486
作者
Lu, Thomas X. [1 ,2 ,3 ]
Munitz, Ariel [1 ]
Rothenberg, Marc E. [1 ]
机构
[1] Univ Cincinnati, Div Allergy & Immunol, Coll Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
[2] Univ Cincinnati, Grad Program Mol & Dev Biol, Coll Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
[3] Univ Cincinnati, Phys Scientist Training Program, Coll Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
基金
美国国家卫生研究院;
关键词
TUMOR-SUPPRESSOR GENE; IN-SITU DETECTION; ASTHMA PATHOGENESIS; LUNG-DISEASE; MOUSE LUNG; TARGETS; CELLS; CANCER; DIFFERENTIATION; MIR-21;
D O I
10.4049/jimmunol.0803560
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 alpha 1 dependent, allergen-induced miR-21 expression was mediated mainly independent of IL-13R alpha 1 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 Journal of Immunology, 2009, 182: 4994-5002.
引用
收藏
页码:4994 / 5002
页数:9
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