Abstract
BackgroundAt present, nothing is known of the role of miRNAs in the immune response in vivo despite the fact that inflammation is thought to underlie multiple acute and chronic diseases. In these circumstances, patients are commonly treated with corticosteroids such as dexamethasone.ResultsTo address this question, we have examined the differential expression of 104 miRNAs using real-time PCR during the innate immune response in mouse lung following exposure to aerosilised lipopolysaccharide (LPS). Following challenge, we observed rapid and transient increase in both the mean (4.3-fold) and individual levels of miRNA expression (46 miRNAs) which peaked at 3 hrs. Crucially, this increase was correlated with a reduction in the expression of tumour necrosis factor (TNF)-α, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, suggesting a potential role for miRNAs in the regulation of inflammatory cytokine production. Examination of the individual miRNA expression profiles showed time dependent increases in miR-21, -25, -27b, -100, 140, -142-3p, -181c, 187, -194, -214, -223 and -224. Corticosteroid studies showed that pre-treatment with dexamethasone at concentrations that inhibited TNF-α production, had no effect either alone or upon the LPS-induced miRNA expression profile.ConclusionWe have shown that the LPS-induced innate immune response is associated with widespread, rapid and transient increases in miRNA expression in the mouse lung and we speculate that these changes might be involved in the regulation of the inflammatory response. In contrast, the lack of effect of dexamethasone in either control or challenged animals implies that the actions of glucocorticoids per se are not mediated through changes in miRNAs expression and that LPS-induced increases in miRNA expression are not mediated via classical inflammatory transcription factors.
Highlights
At present, nothing is known of the role of miRNAs in the immune response in vivo despite the fact that inflammation is thought to underlie multiple acute and chronic diseases
Within the guide strand the specificity is thought to be primarily mediated by the 'seed' region localised at residues 2–8 at the 5' end [16] recent studies have shown that their biological activity is influenced by a number of additional factors including the number of miRNA-recognition elements (MRE) binding sites [17], the distance between MRE binding sites [18] and the higher order structure of the target mRNA [19]
The timedependent changes in the miRNA expression profile in RNA purified from whole mouse lung at 1 hr, 3 hrs and 6 hrs were measured using a novel RT-PCR based approach [43]
Summary
At present, nothing is known of the role of miRNAs in the immune response in vivo despite the fact that inflammation is thought to underlie multiple acute and chronic diseases. Initial studies implicated RNAi in the cellular response to viral infection following the demonstration that virally-derived double stranded RNA was cleaved by the action of the RNase-III-type enzyme Dicer, to produce the characteristic RNA duplexes. These were called short interference RNA (siRNA) in order to differentiate them from longer double stranded RNA (> 30 nucleotide duplexes) that induced an interferon-mediated anti-viral response. Within the guide strand the specificity is thought to be primarily mediated by the 'seed' region localised at residues 2–8 at the 5' end [16] recent studies have shown that their biological activity is influenced by a number of additional factors including the number of MRE binding sites [17], the distance between MRE binding sites [18] and the higher order structure of the target mRNA [19]
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