Effect of miR-19a and miR-21 on the JAK/STAT signaling pathway in the peripheral blood mononuclear cells of patients with systemic juvenile idiopathic arthritis

Li, Hongwei; Xie, Ying; Li, Feng; Sun, Guangchao; Chen, Zhi; Zeng, Huasong

doi:10.3892/etm.2016.3188

Cited by 24 publications

(22 citation statements)

References 33 publications

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“…7A). A recent report demonstrated that miR-19a targets SOCS3 and modulates JAK-STAT signaling in juvenile idiopathic arthritis (14). We first determined SOCS3 expression from primary HSC exposed to HCV-exo.…”

Section: Resultsmentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

145

157

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Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor ␤ (TGF-␤) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection.IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCVinfected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-␤ pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection. KEYWORDS hepatitis C virus, exosomes, miRNAs, liver fibrosis, hepatic stellate cells, microRNA H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus with a genome size of 9.6 kb that encodes several structural and nonstructural proteins. About 170 million people are infected with HCV worldwide. Chronic HCV infection often results in the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCVassociated liver fibrosis is a key pathological process leading to liver cirrhosis and HCC (1, 2), although the underlying mechanisms of disease progression remain unclear. Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis (3). Liver injury is characterized by a phenotypic and functional transformation of normally

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Section: Resultsmentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

145

157

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“…In our previous study [17], thirty-three active phase JIA patients, aged from 2 to 14 years, who were seen in the Rheumatology Department of Guangzhou Women and Children's Medical Center, May 2017-July 2018, were included in this study. They belonged to two subgroups of JIA: systemic juvenile idiopathic arthritis (sJIA) (data were reported in a previous publication) [17] and polyarticular juvenile idiopathic arthritis (pJIA), conforming to the JIA classification of the 2001 International League of Associations for Rheumatology [18]. Twenty normal control patients were recruited from the Health Care Section of the hospital (the control data were reported in the previous publication) [17].…”

Section: Baseline Collectionmentioning

confidence: 99%

“…In our previous study [17], we have explored the relationship between miR-21 and JAK/STAT signal pathway in rheumatoid peripheral blood mononuclear cells (PBMCs). However, it still has not been identified if miR-21 can exert its function by combining STAT3 directly.…”

Section: Introductionmentioning

confidence: 99%

Regulation of JAK/STAT signal pathway by miR-21 in the pathogenesis of juvenile idiopathic arthritis

Zeng

2019

World J Pediatr

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Background Overexpression of the components of the Janus kinase/signal transducer and activator of transcription (JAK/ STAT) signalling pathway is the key factor of the pathogenic mechanisms underlying systemic juvenile idiopathic arthritis (sJIA). The study aims to investigate the association between miR-21 and the JAK/STAT signal pathway in JIA. Methods Total RNA was extracted from peripheral blood mononuclear cells (PBMCs) in active JIA patients. The relative expressions of miR-21, STAT3 and suppressor of cytokine signalling 3 in PBMCs were measured by real-time polymerase chain reaction and their expressions were measured by western blotting and dual-luciferase reported assay. Rheumatoid arthritis fibroblast-like synovial cell (RASF) was stimulated to become to osteoclasts using macrophage colony-stimulating factor (M-CSF) and factors that can impact on their differentiation ability were identified through the transfection of LV3-miR-21. The expression of STAT3/p-STAT3 was measured by western blot, and the levels of interleukin (IL)-17A, p65, matrix metalloproteinases (MMP)-3, MMP-4 and receptor activator of nuclear factor-κB after the LV3-miR-21 transfection were tested by enzyme-linked immunosorbent assay. Finally, the miR-21 targeted STAT3 gene was detected by the dualluciferase reported assay. Results The expression of miR-21 was significantly lower in JIA patients than in healthy control (P < 0.05). The level of STAT3 was increased in PBMCs of JIA group compared with control group (P < 0.05). Furthermore, the expression levels of miR-21 in sJIA and polyarticular JIA groups were negatively correlated with STAT3 (r = − 0.5854/r = − 0.6134, P < 0.05). The expression of STAT3 changed little in PBMCS after the stimulation of IL-6 and not in RASFs with transfection of LV3-miR-21. The expression of p-STAT3 decreased after the stimulation of IL-6 in RASFs transfected by LV3-miR-21 (P < 0.05). RASFs were induced into osteoclasts using M-CSF. The number of osteoclasts as determined by tartrate-resistant acid phosphatase staining was significantly lower in group miR-21 mimics as compared with the negative control group (P < 0.05). Conclusions We showed that expression of miR-21 was significantly lower in JIA patients compared with healthy control. MiR-21 might affect the JAK/STAT signal pathway by suppressing the expression of STAT3 and phosphorylation of STAT3. MiR-21 could inhibit the production of osteoclasts induced from RASFs by M-CSF.

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“…Epigenetic factors including microRNA are potent modifiers of gene expression programs, and as such there is burgeoning interest in defining their roles in inflammation and rheumatic diseases. Indeed, several reports have highlighted altered circulating or cellular microRNA levels in SJIA . Our previous monocyte microRNA expression profiling identified a broad spectrum of microRNA with altered expression in children with active SJIA .…”

Section: Discussionmentioning

confidence: 74%

MicroRNA networks associated with active systemic juvenile idiopathic arthritis regulate CD163 expression and anti-inflammatory functions in macrophages through two distinct mechanisms

Tan

Bennett

et al. 2017

Journal of Leukocyte Biology

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Summary sentence: MicroRNAs utilize multiple mechanisms to regulate CD163 expression and integrate well-characterized macrophage phenotypes and functional properties seen in active systemic juvenile idiopathic arthritis. AbstractSystemic juvenile idiopathic arthritis (SJIA) is a severe childhood arthropathy with features of autoinflammation. Monocytes and macrophages in SJIA have a complex phenotype with both pro-and anti-inflammatory properties that combine features of several well characterized in vitro conditions used to activate macrophages. An important anti-inflammatory phenotype is expression of CD163, a scavenger receptor that sequesters toxic pro-inflammatory complexes that is highly expressed in both active SJIA and macrophage activation syndrome (MAS). CD163 is most strongly up-regulated by IL-10 (M(IL-10)), and not by other conditions that reflect features seen in SJIA monocytes such as M(LPS+IC). MicroRNA plays key roles in integrating cellular signals such as those in macrophage polarization, and as such we hypothesize microRNAs regulate macrophage functional responses in SJIA including CD163 expression. We find that 2 microRNAs previously found to be elevated in active SJIA, miR-125a-5p and miR-181c, significantly reduced macrophage CD163 expression through 2 distinct mechanisms. Neither microRNA was elevated in M(IL-10) with robust CD163 expression, but were instead induced in M(LPS+IC) where they restricted CD163 mRNA expression. Mir-181 species directly targeted CD163 mRNA for degradation. In contrast, miR-125a-5p functions indirectly, as transcriptome analysis of miR125a-5p overexpression identified "cytokine-cytokine receptor interactions" as the most significantly repressed gene pathway, including decreased IL10RA, required for IL-10-mediated CD163 expression. Finally, overexpression of miR-181c inhibited CD163 anti-inflammatory responses to hemoglobin or high mobility group box 1 (HMGB1) complexes. Together, these data show that microRNA utilizes multiple mechanisms to integrate well-characterized polarization phenotypes and regulate macrophage functional properties seen in SJIA.

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Effect of miR-19a and miR-21 on the JAK/STAT signaling pathway in the peripheral blood mononuclear cells of patients with systemic juvenile idiopathic arthritis

Cited by 24 publications

References 33 publications

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Regulation of JAK/STAT signal pathway by miR-21 in the pathogenesis of juvenile idiopathic arthritis

MicroRNA networks associated with active systemic juvenile idiopathic arthritis regulate CD163 expression and anti-inflammatory functions in macrophages through two distinct mechanisms

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