Long noncoding RNA IL6‐AS1 is highly expressed in chronic obstructive pulmonary disease and is associated with interleukin 6 by targeting miR‐149‐5p and early B‐cell factor 1

Yi, Erkang; Zhang, Jiahuan; Zheng, Mengning; Zhang, Yi; Liang, Chunxiao; Hao, Bin; Wang, Hong; Lin, Biting; Pu, Jinding; Lin, Zhiwei; Huang, Peiyu; Li, Bing; Zhou, Yumin; Ran, Pixin

doi:10.1002/ctm2.479

Cited by 33 publications

(42 citation statements)

References 74 publications

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“…EGFR-mediated signaling is likely to be the predominant driver of airway remodeling and mucus cell hyperplasia in CS-induced COPD pathogenesis, and this pathway may not involve SPDEF-mediated mucous responses ( 11 , 37 ). In terms of molecular regulation of other inflammatory factors' expression, lncRNAs are shown to act as molecular sponges/scaffolds for miRNAs as reported recently in COPD ( 38 – 40 ). For example, lncRNA TUG1 promotes airway remodeling via suppressing the miR-145-5p in CS-induced COPD models.…”

Section: Discussionmentioning

confidence: 66%

Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia

et al. 2022

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Research ImpactCigarette smoke (CS) exposure is strongly associated with chronic obstructive pulmonary disease (COPD). In respiratory airways, CS exposure disrupts airway barrier functions, mucous/phlegm production, and basic immune responses of airway epithelial cells. Based on our recent identification of a specific immunomodulatory long noncoding RNA (lncRNA), we investigated its role in CS-induced responses in bronchial airways of cynomolgus macaque model of CS-induced COPD and in former smokers with and without COPD. The lncRNA was significantly upregulated in CS-induced macaque airways and in COPD airways that exhibited higher mucus expression and goblet cell hyperplasia. Experimental models of cells derived from COPD subjects recapitulated the augmented inflammation and mucus expression following the smoke challenge. Blocking of lncRNA expression in cell culture setting suppressed the smoke-induced and COPD-associated dysregulated mucoinflammatory response suggesting that this airway specific immunomodulatory lncRNA may represent a novel target to mitigate the smoke-mediated inflammation and mucus hyperexpression.RationaleIn conducting airways, CS disrupts airway epithelial functions, mucociliary clearances, and innate immune responses that are primarily orchestrated by human bronchial epithelial cells (HBECs). Mucus hypersecretion and dysregulated immune response are the hallmarks of chronic bronchitis (CB) that is often exacerbated by CS. Notably, we recently identified a long noncoding RNA (lncRNA) antisense to ICAM-1 (LASI) that mediates airway epithelial responses.ObjectiveTo investigate the role of LASI lncRNA in CS-induced airway inflammation and mucin hyperexpression in an animal model of COPD, and in HBECs and lung tissues from former smokers with and without COPD. To interrogate LASI lncRNA role in CS-mediated airway mucoinflammatory responses by targeted gene editing.MethodsSmall airway tissue sections from cynomolgus macaques exposed to long-term mainstream CS, and those from former smokers with and without COPD were analyzed. The structured-illumination imaging, RNA fluorescence in-situ hybridization (FISH), and qRT-PCR were used to characterize lncRNA expression and the expression of inflammatory factors and airway mucins in a cell culture model of CS extract (CSE) exposure using HBECs from COPD (CHBEs) in comparison with cells from normal control (NHBEs) subjects. The protein levels of mucin MUC5AC, and inflammatory factors ICAM-1, and IL-6 were determined using specific ELISAs. RNA silencing was used to block LASI lncRNA expression and lentivirus encoding LASI lncRNA was used to achieve LASI overexpression (LASI-OE).ResultsCompared to controls, LASI lncRNA was upregulated in CS-exposed macaques and in COPD smoker airways, correlating with mucus hyperexpression and mucus cell hyperplasia in severe COPD airways. At baseline, the unstimulated CHBEs showed increased LASI lncRNA expression with higher expression of secretory mucin MUC5AC, and inflammatory factors, ICAM-1, and IL-6 compared to NHBEs. CSE exposure of CHBEs resulted in augmented inflammation and mucus expression compared to controls. While RNA silencing-mediated LASI knockdown suppressed the mucoinflammatory response, cells overexpressing LASI lncRNA showed elevated mRNA levels of inflammatory factors.ConclusionsAltogether, LASI lncRNA may represent a novel target to control the smoke-mediated dysregulation in airway responses and COPD exacerbations.

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Section: Discussionmentioning

confidence: 66%

Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia

et al. 2022

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“…Existing research indicated that epigenetic mechanisms are associated with the disease progression in COPD ( 166 ). A novel lncRNA, interleukin 6 antisense RNA 1 (IL6-AS1) supposed to recruit early B-cell factor 1 to the IL-6 promoter to increase the H3K4 methylation and H3K27 acetylation, therein, increases airway inflammation in COPD ( 27 ). SUV39H1 is a histone methyltransferase; the levels of SUV39H1 and H3K9me3 were reduced in COPD patients.…”

Section: Histone Modifications In Inflammatory Diseasesmentioning

confidence: 99%

Role of Histone Post-Translational Modifications in Inflammatory Diseases

et al. 2022

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Inflammation is a defensive reaction for external stimuli to the human body and generally accompanied by immune responses, which is associated with multiple diseases such as atherosclerosis, type 2 diabetes, Alzheimer’s disease, psoriasis, asthma, chronic lung diseases, inflammatory bowel disease, and multiple virus-associated diseases. Epigenetic mechanisms have been demonstrated to play a key role in the regulation of inflammation. Common epigenetic regulations are DNA methylation, histone modifications, and non-coding RNA expression; among these, histone modifications embrace various post-modifications including acetylation, methylation, phosphorylation, ubiquitination, and ADP ribosylation. This review focuses on the significant role of histone modifications in the progression of inflammatory diseases, providing the potential target for clinical therapy of inflammation-associated diseases.

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“…Previous research has shown that the dysregulation of miR-149-5p is closely associated with malignant tumor progression, metastasis, and chemoresistance in gastric cancer (31)(32)(33), papillary thyroid cancer (34), colorectal cancer (35)(36)(37), and breast cancer (38). Additionally, miR-149-5p is also involved in the pathogenesis of inflammationassociated diseases, such as the PM 2.5 -induced inflammatory response (39), rheumatoid arthritis (40), and chronic obstructive pulmonary disease (41). In recent years, it has been reported that miR-149-5p plays crucial roles in cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of LncRNA-HFRL expression induces cardiomyocyte inflammation, proliferation, and fibrosis via the sequestering of miR-149-5p-mediated collagen 22A inhibition

Teng

Tian

et al. 2022

Ann Transl Med

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Background Long non-coding ribonucleic acids (lncRNAs) are believed to play crucial roles in cardiovascular diseases; however, details of the underlying mechanisms by which this occurs remain unclear. Methods A mouse heart failure (HF) model was established using isoproterenol (ISO), and confirmed by immunostaining and echocardiography. RNA-sequencing was performed to screen the differential lncRNA expression profiles and heart failure relative lncRNA (HFRL) was selected as the target which was validated by quantitative real-time polymerase chain reaction (qRT-PCR). In HL-1 cells, the cardiac function, inflammatory, and fibrosis-related genes expression changes were examined by qRT-PCR after silencing of HFRL by lentivirus. Meanwhile, Cell Counting Kit-8 (CCK-8) assays were used to detect the effects of HFRL on the cell proliferation and viability. Reactive oxygen species (ROS) assays were also used to explore the role of HFRL in oxidative damage. Next, bioinformatics analysis was conducted to predict the potential binding microRNAs (mmu-miR-149-5p) to HFRL, which was confirmed by RNA-pulldown assays. The target gene of miR-149-5p was also predicted and further validated by Dual-luciferase reporter assays, qRT-PCR, and western blot. To investigate the synergistic regulatory effect of HFRL and miR-149-5p, HL-1 cells were infected with the lentivirus of HFRL with or without simultaneous knockdown of miR-149-5p. Then, qRT-PCR and western blot were used to examine cardiac function, inflammatory, and fibrosis-related gene expression changes, respectively. In HL-1 cells, CCK-8 assays were performed to detect the proliferation and viability. ROS assays were used to explore the oxidative damage. Results The administration of ISO induced mice fibrosis, inflammation, and HF. The in-vitro results showed that knockdown of HFRL suppressed cardiomyocyte proliferation and viability, attenuated inflammatory, cardiac function, and fibrosis-related gene expression, and promoted oxidative damage. HFRL was found to bind to mmu-miR-149-5p and inversely target the 3'-untranscripted region of the collagen 22A1 gene. Thus, HFRL affected cardiomyocyte inflammation, proliferation, viability, oxidative damage, and pro-fibrotic function via sequestration to miR-149-5p. Conclusions The HFRL/miR-149-5p axis plays an important role in regulating cardiac inflammation, proliferation, and fibrosis via a synergistic effect, which suggests that HFRL might be a novel target for HF.

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Long noncoding RNA IL6‐AS1 is highly expressed in chronic obstructive pulmonary disease and is associated with interleukin 6 by targeting miR‐149‐5p and early B‐cell factor 1

Cited by 33 publications

References 74 publications

Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia

Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia

Role of Histone Post-Translational Modifications in Inflammatory Diseases

Enhancement of LncRNA-HFRL expression induces cardiomyocyte inflammation, proliferation, and fibrosis via the sequestering of miR-149-5p-mediated collagen 22A inhibition

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