Dysregulated interleukin-23 signalling contributes to the increased collagen production in scleroderma fibroblasts via balancing microRNA expression

Nakayama, Wakana; Jinnin, Masatoshi; Tomizawa, Yukiko; Nakamura, Kayo; Kudo, Hideo; Inoue, Kuniko; Makino, Katsunari; Honda, Noritoshi; Kajihara, Ikko; Fukushima, Satoshi; Ihn, Hironobu

doi:10.1093/rheumatology/kew336

Cited by 30 publications

(15 citation statements)

References 29 publications

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“…Meanwhile, the conventional hallmark of fibrosis is characterized by the accumulation of various fibrillar collagens, which principally serve as a marker of fibrosis, especially of Collagen 1 [24]. More notably, previous studies have demonstrated that miR-18a can diminish the expression of Collagen 1 via interleukin-23 [25]. Further in line with our findings, Yang et al [26] demonstrated that the involvement of miR-18a in the signaling pathway of TGF-β1 by mediation of CCN2.…”

Section: Discussionsupporting

confidence: 87%

The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure

Jin

Wang

et al. 2021

Cell Biosci

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Background Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3. Methods Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry. Results HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and −dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined. Conclusion Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.

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Section: Discussionsupporting

confidence: 87%

The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure

Jin

Wang

et al. 2021

Cell Biosci

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“…The evidence that enthesopathy in SSc and SpA shares the same micro-anatomical involvement and features suggests a possible common pathogenetic cascade across these two different diseases. In SSc, it has been shown that IL-23 and IL-17 up-regulate collagen production in fibroblasts, a process that could be significantly reduced by an IL-17-blocking antibody [25,26]. On this basis, it can be speculated that an altered IL-23/IL-17 axis might play a role also in SScrelated enthesopathy.…”

Section: Discussionmentioning

confidence: 99%

Enthesopathy and involvement of synovio-entheseal complex in systemic sclerosis: an ultrasound pilot study

et al. 2019

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Objectives SSc is a chronic autoimmune disease characterized by inflammation of the skin and multiple internal organs. Articular involvement is one of the main features of SSc, and typical hallmarks of SpA have been found in SSc patients. The aim of the present study was to estimate the prevalence of entheseal and synovio-entheseal complex (SEC) alterations in a cohort of SSc patients. Methods One hundred SSc patients and 25 healthy subjects were included in this cross-sectional study. The enthesis sites of lateral epicondylar common extensor tendons (CET) and the enthesis of the Glasgow Ultrasound Enthesis Scoring System were evaluated. SEC involvement was evaluated only at CET enthesis. Results In SSc, the Glasgow Ultrasound Enthesis Scoring System score was significantly higher (median 4.0, interquartile range 2.0–7.0) than in controls (median 1.0, interquartile range 0.0–3.0) (P < 0.0001). CET enthesis of SSc patients showed more frequent US B-mode alterations than that of controls (χ2 = 11.47, P = 0.0007 for size; χ2 = 13.79, P = 0.0002 for cortical irregularity, χ2 = 5.24, P = 0.022 for calcification/enthesophytes). Power Doppler US signal at CET enthesis was significantly more frequent in SSc patients than in healthy controls (χ2 = 9.11, P = 0.0025), as was the concomitant SEC involvement (χ2 = 8.52, P = 0.0035). Conclusion These data show that SSc patients frequently present US features of enthesopathy. Moreover, CET enthesopathy was correlated with SEC inflammation, suggesting that entheseal inflammation in SSc may share the same micro-anatomical targets as found in SpA.

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“…In addition to AS, IL-23 is also involved in the pathogenesis of several other autoimmune diseases, such as inflammatory bowel disease and psoriasis, which all belong to the category of spondyloarthritis [ 21 ]. However, few studies have addressed the possible effect of IL-23 on the regulation of miRNA expression [ 22 – 24 ]. In this study, K562 cells instead of Jurkat cells were used as a platform for screening the IL-23-regulated miRNA expression because Jurkat cells had low expression levels of IL-23 receptor compared with K562 cells [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis

Lai

Tung

et al. 2018

Arthritis Res Ther

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BackgroundInterleukin (IL)-23 can facilitate the differentiation of IL-17-producing helper T cells (Th17). The IL-23/IL-17 axis is known to play a key role in the immunopathogenesis of ankylosing spondylitis (AS). We hypothesized that the expression of microRNAs (miRNAs, miRs) would be regulated by IL-23 and that these miRNAs could participate in the immunopathogenesis of AS.MethodsExpression profiles of human miRNAs in K562 cells, cultured in the presence or absence of IL-23 for 3 days, were analyzed by microarray. Potentially aberrantly expressed miRNAs were validated using T-cell samples from 24 patients with AS and 16 control subjects. Next-generation sequencing (NGS) was conducted to search for gene expression and biological functions regulated by specific miRNAs in the IL-23-mediated signaling pathway.ResultsInitial analysis revealed that the expression levels of 12 miRNAs were significantly higher, whereas those of 4 miRNAs were significantly lower, in K562 cells after coculture with IL-23 for 3 days. Among these IL-23-regulated miRNAs, the expression levels of miR-29b-1-5p, miR-4449, miR-211-3p, miR-1914-3p, and miR-7114-5p were found to be higher in AS T cells. The transfection of miR-29b-1-5p mimic suppressed IL-23-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation in K562 cells. After NGS analysis and validation, we found that miR-29b-1-5p upregulated the expression of angiogenin, which was also upregulated in K562 cells after coculture with IL-23. Increased expression of miR-29b-1-5p or miR-211-3p could enhance interferon-γ expression.ConclusionsAmong the miRNAs regulated by IL-23, expression levels of five miRNAs were increased in T cells from patients with AS. The transfection of miR-29b-1-5p mimic could inhibit the IL-23-mediated STAT3 phosphorylation and might play a role in negative feedback control in the immunopathogenesis of AS.

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Dysregulated interleukin-23 signalling contributes to the increased collagen production in scleroderma fibroblasts via balancing microRNA expression

Cited by 30 publications

References 29 publications

The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure

The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure

Enthesopathy and involvement of synovio-entheseal complex in systemic sclerosis: an ultrasound pilot study

Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis

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