Dataset Information

Proinflammatory role for let-7 microRNAS in experimental asthma.

ABSTRACT: MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3'-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking. Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model of asthma. Deep sequencing and microarray analyses of the mouse lung short RNAome revealed numerous extant and novel miRNAs and other transcript classes. Similar to mRNAs, lung miRNA expression changed dynamically during the transition from the naive to the allergic state, suggesting numerous functional relationships. A possible role for miRNA editing in altering the lung mRNA target repertoire was also identified. Multiple members of the highly conserved let-7 miRNA family were the most abundant lung miRNAs, and we confirmed in vitro that interleukin 13 (IL-13), a cytokine essential for expression for allergic lung disease, is regulated by mmu-let-7a. However, inhibition of let-7 miRNAs in vivo using a locked nucleic acid profoundly inhibited production of allergic cytokines and the disease phenotype. Our findings thus reveal unexpected complexity in the miRNAome underlying allergic lung disease and demonstrate a proinflammatory role for let-7 miRNAs.

SUBMITTER: Polikepahad S

PROVIDER: S-EPMC2943272 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Proinflammatory role for let-7 microRNAS in experimental asthma.

Polikepahad Sumanth S Knight John M JM Naghavi Arash O AO Oplt Toni T Creighton Chad J CJ Shaw Chad C Benham Ashley L AL Kim Jong J Soibam Benjamin B Harris R Alan RA Coarfa Cristian C Zariff Azam A Milosavljevic Aleksandar A Batts Lakeisha M LM Kheradmand Farrah F Gunaratne Preethi H PH Corry David B DB

The Journal of biological chemistry 20100714 39

MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3'-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking. Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model ...[more]

PMID: 20630862

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Project description:Background: Several studies indicate that asthma is a polygenic disease, and its complexity originates from the interaction of an unknown number of genes with environmental factors. Objective: In this study we aimed to identify new genes, gene groups and pathways involved in the pathogenesis of experimental asthma. Methods: In an ovalbumin-induced murine model of asthma we applied microarray gene expression analysis of the lung at different time points in the asthmatic process. Advanced statistical methods were used to relate gene expression changes to cellular processes and to integrate our results into multiple levels of information available in public databases. Results: According to the observed marked neutrophil infiltration found early, at 4 hours after the first allergen challenge, gene expression pattern reflected mainly an acute inflammatory response and strong chemotactic activity. At 24 hours after the third allergen challenge, gene set enrichment analysis revealed significant overrepresentation of gene sets corresponding to Th2 type inflammation models. Among the top downregulated transcripts, an antioxidant enzyme, paraoxonase-1 (PON1) was identified. Reduced PON1 protein expression in the lung was confirmed by immunohistochemical analysis. In human asthmatic patients we found that serum PON1 activity was reduced at exacerbation, but increased parallel with improving asthma symptoms. PON1 gene polymorphisms did not influence the susceptibility to the disease. Conclusion: Our observations suggest that an altered PON1 activity might be involved in the pathogenesis of asthma, and PON1 might be a potential new therapeutic target as well as a new diagnostic tool for following up the effect of therapy. Experiment Overall Design: Experimental design: Experiment Overall Design: Three groups of mice (6 mice/group) were sensitized and challenged with allergen (OVA), one group (control group) was sensitized and challenged with placebo (PBS) and served as a control. On day 28 and 30, 4 h after the first and third allergen challenge, mice in groups 1 and 2 were anaesthetized by an intraperitoneal injection of ketamine and xylazine, BAL was isolated and the lungs were removed for further analysis. On day 31, 24h after the third (last) allergen challenge mice in group 3 and the controls were anaesthetized, and airway hyper-responsiveness (AHR) was assessed. After the AHR measurements, BAL sampling and lung tissue collection were performed, the same way as it was carried out in groups 1 and 2. Cellular composition of BAL, and lung histology were examined in all mice in all groups. AHR was measured in controls and group 3 on day 31. 1000 ng-1000 ng quality-checked total lung tissue RNA samples from OVA sensitized and challenged mice from group 1, 2 and 3 were identically labeled with Cy5 dye, while lung tissue RNA samples from group 4 (control, placebo sensitized and challenged) were pooled and labeled with Cy3 dye, and served as a common reference.

Dataset Information

Proinflammatory role for let-7 microRNAS in experimental asthma.

Publications

Proinflammatory role for let-7 microRNAS in experimental asthma.

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