Long Non-coding RNAs Regulate Lung Fibroblasts’ Inflammation, Proliferation, Study Shows

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Proliferation and inflammation of human lung fibroblasts is controlled by small RNA molecules called long non-coding RNAs, a study reports.

The study, “Long intergenic non-coding RNAs regulate human lung fibroblast function: Implications for idiopathic pulmonary fibrosis,” was published in the journal Nature Scientific Reports.

While the cause of idiopathic pulmonary fibrosis (IPF) remains unclear, analysis of lung fibroblasts — the cells responsible for fibrosis — from IPF patients show that these cells have different proliferation rates and release of pro-fibrotic factors, compared to those from patients with non-fibrotic diseases.

The cell’s different behavior may be linked with differences in gene regulation.

Long non-coding RNAs are small RNA molecules that regulate the activity (expression) of genes involved in several biological functions. However, little is known about the role of long non-coding RNAs in lung fibroblasts’ function and IPF.

Researchers compared the functional responses of lung fibroblasts from IPF patients and controls.

Results showed that IPF fibroblasts were more fibrotic then control fibroblasts, as shown by an increased sensitivity to TGF-β1 activation, a pro-fibrotic factor.

IPF lung fibroblasts also showed a reduced proliferation rate, and were less inflammatory when compared to control fibroblasts, as shown by a reduced release of interleukin (IL)-6 in response to treatment with the pro-inflammatory factor IL-1 beta.

Researchers then evaluated whether the differences in fibroblast responses were linked to epigenetic differences. Epigenetics refers to changes that are external modifications to DNA that can turn genes on or off without altering the actual DNA sequence.

Indeed, researchers identified differences in epigenetic marks, called histone modifications, between control and IPF fibroblasts.

They then assessed the role of long non-coding RNAs as mediators of the differences in behavior between IPF and control fibroblasts.

After comparing the profile of long non-coding RNAs between both conditions, researchers identified two of these RNAs — called LINC00960 and LINC01140 — whose levels were higher in IPF fibroblasts compared to controls. Analysis of RNA sequencing of lung biopsies confirmed the increased expression of LINC01140 but not LINC00960.

A functional assay to decrease the levels of both long non-coding RNAs showed that they had no effect on the fibrotic response.

On the contrary, decreasing the levels of both long non-coding RNAs reduced the proliferation of both control and IPF fibroblasts in basal conditions, and when treated with a proliferation inducer called PDGF.

Decreasing the levels of LINC01140, but not LINC00960, increased the inflammatory response, which was greater in IPF compared to control fibroblasts.

Overall, these results “demonstrate for the first time that [long non-coding RNAs] are important regulators of proliferation and inflammation in human lung fibroblasts, and that these might mediate the reduced inflammatory response observed in IPF-derived fibroblasts,” the team concluded.

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