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

Abstract

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 over-expression of miR-21 and under-expression of miR-1 in the induced IL-13 transgenic mice compared to control mice. These findings were validated in two independent models of allergen-induced allergic airway inflammation and in IL-4 lung transgenic mice. While IL-13 induced miR-21 expression was IL-13 receptor alpha 1 dependent, allergen induced miR-21 expression was mediated mainly independent of IL-13 receptor alpha 1 and STAT6. Notably, predictive algorithms identified potential direct miR-21 targets among IL-13-regulated lung transcripts such as IL-12p35 mRNA that was decreased in IL-13 transgenic mice. Introduction of pre-miR-21 dose-dependently inhibited cellular expression of a reporter vector harboring the 3’UTR of IL-12p35. Moreover, mutating miR-21 binding sites in IL-12p35 3’UTR 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 T helper cell polarization.

MicroRNAs in the regulation of TLR and RIG-I pathways

“…Il-12p35 mRNA can be targeted by miR-21 in macrophages and DCs, leading to restricted adaptive Th1 responses. [99][100][101] miR-106 has been demonstrated to target Il-10 mRNA, 102 while miR-29 suppresses immune responses against intracellular pathogens by targeting IFN-c. 103 Numerous cytokine encoding mRNAs are regulated by RNA-binding proteins (RBPs) through the AU-rich elements in their 39-UTR, which may play a vital role in mRNA stabilization. MiRNAs can also cooperate with these RBPs to regulate mRNA stability or translation.…”

Changes in microRNA expression in rat lungs caused by sevoflurane anesthesia: a TaqMan^|^reg; low-density array study

“…Some of the differentially expressed 28 miRNAs are known to be involved in inflammatory lung diseases and PAH. For example, miR-126, -21, and -26a are important in asthma (17,18,21); let7d, miR-21, -155, and -29 are important in IPF (26); and miR-146a, -155, -21, -25, and -26a are important in PAH (14). Here, we found that expression of each of these miRNA was significantly changed by sevoflurane anesthesia; therefore, sevoflurane anesthesia may affect lung diseases such as asthma, IPF, and PAH.…”

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…Furthermore, mutating miR-21 binding sites in IL-12p35 3'-untranslated region abrogated miR-21-mediated repression. Thus, IL-12p35 is likely the direct target of miR-21 (Lu et al, 2009b). These researchers further generated miR-21 deficient mice.…”

“…miR-21 was initially identified to inhibit IL-12p35 in a reporter system (Lu et al, 2009b). Furthermore, mutating miR-21 binding sites in IL-12p35 3'-untranslated region abrogated miR-21-mediated repression.…”