Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Abstract

Cystic Fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyperexpression of IL-8 protein. However, the mechanistic link between mutations in CFTR and acquisition of the proinflammatory phenotype in the CF airway has remained elusive. We hypothesized that specific microRNAs (miRNAs) might mediate this linkage. To identify the potential link, we screened an miRNA library for differential expression in ⌬F508-CFTR and wild type CFTR lung epithelial cell lines. Of 22 differentially and significantly expressed miRNAs, we found that expression of miR-155 was more than 5-fold elevated in CF IB3-1 lung epithelial cells in culture, compared with control IB3-1/S9 cells. Clinically, miR-155 was also highly expressed in CF lung epithelial cells and circulating CF neutrophils biopsied from CF patients. We report here that high levels of miR-155 specifically reduced levels of SHIP1, thereby promoting PI3K/Akt activation. However, overexpressing SHIP1 or inhibition of PI3K in CF cells suppressed IL-8 expression. Finally, we found that phospho-Akt levels were elevated in CF lung epithelial cells and were specifically lowered by either antagomir-155 or elevated expression of SHIP1. We therefore suggest that elevated miR-155 contributes to the proinflammatory expression of IL-8 in CF lung epithelial cells by lowering SHIP1 expression and thereby activating the PI3K/Akt signaling pathway. These data suggest that miR-155 may play an important role in the activation of IL-8-dependent inflammation in CF.

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“…Furthermore, the reduction of SHIP by miR-155 activates PI3K/AKT activation [87] . mTOR is a direct target of PI3K/AKT activation, which is activated by AKT phosphorylation.…”

Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

“…Recent studies have revealed that miR-155 was involved in the development of inflammatory lung disease (20,21). For example, elevated miR-155 could promote inflammation in the lung in cystic fibrosis disease (22). Global miRNA profile analysis showed that the expression of miR-155 was elevated in ALI (21,23).…”

Ion channels/transporters as epigenetic regulators? —a microRNA perspective

“…Taken together, these results have indicated the importance of ion channels in the regulation of miRNAs in normal physiological conditions, dysfunction of which may lead to clinical manifestations. Interestingly, by comparing wild type and mutant (DF508)-CFTR lung epithelial cell lines, Bhattacharyya et al [62] recently found that 22 miRNAs were differentially expressed in CFTR defective cells. Among them, the expression of miR-155 was more than 5-fold elevated in CF IB3-1 lung epithelial cells compared with control IB3-1/S9 cells, which was suggested to be responsible for the enhanced expression of IL-8 and exaggerated inflammatory response observed in cystic fibrosis (CF).…”