Long intergenic non-coding RNAs regulate human lung fibroblast function: Implications for idiopathic pulmonary fibrosis

Abstract

Phenotypic changes in lung fibroblasts are believed to contribute to the development of Idiopathic Pulmonary Fibrosis (IPF), a progressive and fatal lung disease. Long intergenic non-coding RNAs (lincRNAs) have been identified as novel regulators of gene expression and protein activity. In non-stimulated cells, we observed reduced proliferation and inflammation but no difference in the fibrotic response of IPF fibroblasts. These functional changes in non-stimulated cells were associated with changes in the expression of the histone marks, H3K4me1, H3K4me3 and H3K27ac indicating a possible involvement of epigenetics. Following activation with TGF-β1 and IL-1β, we demonstrated an increased fibrotic but reduced inflammatory response in IPF fibroblasts. There was no significant difference in proliferation following PDGF exposure. The lincRNAs, LINC00960 and LINC01140 were upregulated in IPF fibroblasts. Knockdown studies showed that LINC00960 and LINC01140 were positive regulators of proliferation in both control and IPF fibroblasts but had no effect upon the fibrotic response. Knockdown of LINC01140 but not LINC00960 increased the inflammatory response, which was greater in IPF compared to control fibroblasts. Overall, these studies demonstrate for the first time that lincRNAs 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.

Integrated Transcriptome Analysis of Human Visceral Adipocytes Unravels Dysregulated microRNA-Long Non-coding RNA-mRNA Networks in Obesity and Colorectal Cancer

“…Specifically, in obese subjects we found several lncRNAs (e.g., ZFAS1, LUCAT1, HIF1A-AS1, HOXB-AS3) already identified in the setting of different type of cancers, but not previously reported in human AT. Moreover, the lncRNA MIR3142HG, recently described as important mediator of the inflammatory response in Idiopathic Pulmonary Lung Fibroblasts positively regulating CXCL8 and CCL2 release (68), is specifically up-modulated in obesity. Notably, we previously reported an upregulation of both CCL2 and CXCL8 in adipocytes from Ob individuals (29), suggesting a role of this lncRNA in the AT inflammation.…”

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

“…LINC01140 and LINC0090 were also found to be upregulated in isolated IPF fibroblasts, and LINC01140 was also upregulated in IPF biopsies and was shown to be a negative regulator of the inflammatory response [84]. Knockdown studies have also demonstrated that both lncRNAs play a role in mediating proliferation with and without PDGF-stimulation in both control and IPF fibroblasts.…”

“…As well as biopsies, gene expression in isolated human lung fibroblasts has also been employed to examine and identify novel IPF-related genes and pathways. A recent microarray study identified several IPF-associated genes upregulated in both lung control and IPF fibroblasts in response to TGF-β1 [84]. Another study by Lee et al, identified CCL8 expression to be elevated in IPF lung fibroblasts using microarrays [43].…”

Decrypting the crosstalk of noncoding RNAs in the progression of IPF

“…An up-to-date study revealed that the upregulation of certain lincRNAs, namely LINC00960 and LINC01140, and knockdown of LINC01140 but not LINC00960, stimulates the inflammatory response in IPF fibroblasts. Thus, demonstrating the importance of lincR-NAs as regulators of proliferation and inflammation in IPF for the first time [15]. Dai et al [16] found that the lncRNA MALAT1 could activate the lipopolysaccharide-induced inflammatory response pathway and promote the progression of lung injury in rat models.…”