Long Non-coding RNAs Are Central Regulators of the IL-1β-Induced Inflammatory Response in Normal and Idiopathic Pulmonary Lung Fibroblasts

Abstract

There is accumulating evidence to indicate that long non-coding RNAs (lncRNAs) are important regulators of the inflammatory response. In this report, we have employed next generation sequencing to identify 14 lncRNAs that are differentially expressed in human lung fibroblasts following the induction of inflammation using interleukin-1β (IL-1β). Knockdown of the two most highly expressed lncRNAs, IL7AS, and MIR3142HG, showed that IL7AS negatively regulated IL-6 release whilst MIR3142HG was a positive regulator of IL-8 and CCL2 release. Parallel studies in fibroblasts derived from patients with idiopathic pulmonary fibrosis showed similar increases in IL7AS levels, that also negatively regulate IL-6 release. In contrast, IL-1β-induced MIR3142HG expression, and its metabolism to miR-146a, was reduced by 4- and 9-fold in IPF fibroblasts, respectively. This correlated with a reduced expression of inflammatory mediators whilst MIR3142HG knockdown showed no effect upon IL-8 and CCL2 release. Pharmacological studies showed that IL-1β-induced IL7AS and MIR3142HG production and release of IL-6, IL-8, and CCL2 in both control and IPF fibroblasts were mediated via an NF-κB-mediated pathway. In summary, we have cataloged those lncRNAs that are differentially expressed following IL-1β-activation of human lung fibroblasts, shown that IL7AS and MIR3142HG regulate the inflammatory response and demonstrated that the reduced inflammatory response in IPF fibroblast is correlated with attenuated expression of MIR3142HG/miR-146a.

Newcastle disease virus RNA-induced IL-1β expression via the NLRP3/caspase-1 inflammasome

“…Viruses invade host cells and utilize the host nucleic acids and proteins to induce the synthesis of viral components to produce new virions. Various structural components, such as viral nucleic acids, ion channel proteins, and non-structural proteins produced during the replication process, can activate the expression of IL-1β [28]. Following influenza virus infection, the host cell recognizes viral genomic RNA through TLR7 and increases IL-1β expression, which is dependent upon activation of NLRP3/caspase-1 inflammasomes [5].…”

Impaired lnc‐IL7R modulatory mechanism of Toll‐like receptors is associated with an exacerbator phenotype of chronic obstructive pulmonary disease

“…23 Moreover IL7AS, a synthetically conserved antisense with the IL7 promoter, negatively regulates IL-6 release in response to IL-1β. 28 Nevertheless, lnc-IL7R is believed to work through an irrelevant mechanism. It suppresses the LPS-induced inflammatory response through the epigenetic regulation of histone H3 at K27 trimethylation (H3K27me3) at the proximal promoters of related inflammatory mediators.…”

Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

“…release ( Figure 5), whereas MIR3142HG was found to positively regulate expression and protein release of CCL2 and IL-8. Both lncRNAs were found to be regulated by the NF-κB pathway [139]. Knock-down of IL7AS was shown to elevate both IL-6 mRNA and protein levels, indicating a significant role of this lncRNA in mediating the inflammatory response in human lung fibroblasts.…”

“…Knockdown of IL7AS demonstrated a negative regulatory activity of this lncRNA in IL-6 mRNA expression and protein release ( Figure 5), whereas MIR3142HG was found to positively regulate expression and protein release of CCL2 and Il-8. Both lncRNAs were found to be regulated by the NF-κB pathway [139]. release ( Figure 5), whereas MIR3142HG was found to positively regulate expression and protein release of CCL2 and IL-8.…”