MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes

Philippe, Lucas; Alsaleh, Ghada; Pichot, Angélique; Ostermann, Eléonore; Zuber, Guy; Frisch, Benoı̂t; Sibilia, Jean; Pfeffer, Sébastien; Bahram, Seiamak; Wachsmann, Dominique; Georgel, Philippe

doi:10.1136/annrheumdis-2012-201654

Cited by 108 publications

(70 citation statements)

References 36 publications

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“…22,25,27,28 However, there has been limited research to define the underlying mechanism. The Bim gene expression was inversely associated with miR-20a-5p, suggesting it could be a target gene of miR20a-5p.…”

Section: Mir-20a-5p Regulates Bim Expression Via Jnk2mentioning

confidence: 99%

“…24 In addition, miR-20a also plays an important role in the regulation of proinflammatory cytokine release, such as controlling ASK1 expression, in inflammatory disease. 25 Furthermore, miR-20a was proved to downregulate Fas expression in osteosarcoma, thus increasing the metastatic potential of osteosarcoma cells by allowing survival in the FasLC lung microenvironment. 26 Alternation of miRNA expression profiles has been observed in serum and sputum from TB patients, 14,16 but it still remains unknown in monocytes from peripheral blood.…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

et al. 2016

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Induction of cell apoptosis is one of the major host defense mechanisms through which macrophages control Mycobacterium tuberculosis (Mtb) infection. However, the mechanisms underlying macrophage apoptosis triggered by Mtb infection are still largely unknown. In this study, a microarray profiling survey revealed 14 miRNAs were down-regulated in CD14C monocytes from active pulmonary tuberculosis patients, and only the reduction of miR-20a-5p could be reversed after successful anti-tuberculosis treatment. Validation of miR-20a-5p expression was confirmed using real time qPCR. Moreover, miR-20a-5p expression also decreased in differentiated THP-1 macrophages after mycobacterial infection in vitro. Functional assays through forced or inhibited expression of miR-20a-5p in THP-1 macrophages demonstrated that miR-20a-5p functioned as a negative regulator of mycobacterial-triggered apoptosis. Importantly, inhibition of miR-20a-5p expression resulted in more efficient mycobacterial clearance from infected THP-1 macrophages while miR-20a-5p overexpression promoted mycobacterial survival. Mechanistically, miR-20a-5p was demonstrated to regulate Bim expression in a JNK2-dependent manner, unlike Bcl2, and luciferase assay showed JNK2 was a novel direct target of miR-20a-5p. Together, our findings indicate that downregulation of miR-20a-5p triggers macrophage apoptosis as a novel mechanism for host defense against mycobacterial infection.

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Section: Mir-20a-5p Regulates Bim Expression Via Jnk2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

et al. 2016

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“…MiR-181a regulates inflammatory responses associated with IL-1β levels in LPS-stimulated monocytes [55] and IL-8 levels in human fibroblasts [56]. Transfection of miR-20a mimics in human monocytes decreased the release of IL-1β and TNF-α, and injection of miR-20a mimics in mice led to a global decrease in IL-6 secretion in macrophages that were stimulated with LPS in vitro [57]. Considering that miR-125b, miR-150, miR-203, miR-181a and miR-20a are downregulated in COPD patients and that they all regulate inflammatory processes, it is possible that their alteration is involved in the pro-inflammatory phenotype observed in COPD.…”

Section: Involvement Of Mirnas In Inflammatory Responsesmentioning

confidence: 99%

Unravelling the complexity of COPD by microRNAs: it's a small world after all

et al. 2015

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Chronic obstructive pulmonary disease (COPD) is a progressive lung disease and is currently the fourth leading cause of death worldwide. Chronic inflammation and repair processes in the small airways are characteristic of COPD. Despite extensive efforts from researchers and industry, there is still no cure for COPD, hence an urgent need for new therapeutic alternatives. MicroRNAs are such an option; they are small noncoding RNAs involved in gene regulation. Their importance has been shown with respect to maintaining the balance between health and disease. Although previous reviews have discussed the expression of microRNAs related to lung disease, a detailed discussion regarding the function of differential miRNA expression in the pathogenesis of COPD is lacking.In this review we link the expression of microRNAs to different features of COPD and explain their importance in the pathogenesis of this disease. We further discuss their potential to contribute to the development of future therapeutic strategies. @ERSpublications Complexity of miRNAs in COPD: an up-to-date overview of the role of miRNAs in the different features of COPD http://ow.ly/Pk4FP

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“…In genome-wide miRNA screens to identify effectors of the NF-B pathway in breast cancer cells, miR-373 family members (miR-373 and miR-520) strongly inhibited TNF-␣ signaling by directly targeting a core NF-B signaling component, RELA (p65) (62). Additionally, overexpression of miR-20a in rheumatoid fibroblast-like synoviocytes suppressed IL-6 and CXCL10 release in response to lipopolysaccharide (LPS) treatment; in this context, miR-20a was shown to target apoptosis signal-regulating kinase 1 (ASK1), a critical mitogen-activated protein kinase kinase kinase (MAP3K) component of TLR and TNF signaling pathways (63). These observations raise the possibility that JMRV miR-J8 as well as RRV miR-rR1-8 may target macaque homologs of RELA and/or ASK1.…”

Section: Discussionmentioning

confidence: 99%

Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family

Skalsky

Barr

Jeffery

et al. 2016

J Virol

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Japanese macaque (JM) rhadinovirus (JMRV) is a novel, gamma-2 herpesvirus that was recently isolated from JM with inflammatory demyelinating encephalomyelitis (JME). JME is a spontaneous and chronic disease with clinical characteristics and immunohistopathology comparable to those of multiple sclerosis in humans. Little is known about the molecular biology of JMRV. Here, we sought to identify and characterize the small RNAs expressed during lytic JMRV infection using deep sequencing. Fifteen novel viral microRNAs (miRNAs) were identified in JMRV-infected fibroblasts, all of which were readily detectable by 24 h postinfection and accumulated to high levels by 72 h. Sequence comparisons to human Kaposi's sarcoma-associated herpesvirus (KSHV) miRNAs revealed several viral miRNA homologs. To functionally characterize JMRV miRNAs, we screened for their effects on nuclear factor kappa B (NF-B) signaling in the presence of two proinflammatory cytokines, tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤). Multiple JMRV miRNAs suppressed cytokine-induced NF-B activation. One of these miRNAs, miR-J8, has seed sequence homology to members of the cellular miR-17/20/106 and miR-373 families, which are key players in cell cycle regulation as well as inflammation. Using reporters, we show that miR-J8 can target 3= untranslated regions (UTRs) with miR-17-5p or miR-20a cognate sites. Our studies implicate JMRV miRNAs in the suppression of innate antiviral immune responses, which is an emerging feature of many viral miRNAs. IMPORTANCEGammaherpesviruses are associated with multiple diseases linked to immunosuppression and inflammation, including AIDSrelated cancers and autoimmune diseases. JMRV is a recently identified herpesvirus that has been linked to JME, an inflammatory demyelinating disease in Japanese macaques that mimics multiple sclerosis. There are few large-animal models for gammaherpesvirus-associated pathogenesis. Here, we provide the first experimental evidence of JMRV miRNAs in vitro and demonstrate that one of these viral miRNAs can mimic the activity of the cellular miR-17/20/106 family. Our work provides unique insight into the roles of viral miRNAs during rhadinovirus infection and provides an important step toward understanding viral miRNA function in a nonhuman primate model system. J apanese macaque rhadinovirus (JMRV) is a novel simian herpesvirus that was recently isolated from a central nervous system (CNS) lesion of a Japanese macaque (JM) or snow monkey (Macaca fuscata) with Japanese macaque encephalomyelitis (JME) (1, 2). JME is an inflammatory, demyelinating disease that affects ϳ1 to 3% of the JM colony each year at the Oregon National Primate Research Center (ONPRC) (1). At the clinical and histopathological levels, JME is comparable to multiple sclerosis (MS), an immune-mediated disease, and is the only known spontaneously occurring, natural MS-like disease in nonhuman primates (NHP). Animals with JME present with ataxia and progressive paralysis and at the pathological level exh...

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MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes

Abstract: Our data point toward an important role for miR-20a in the regulation of pro-inflammatory cytokines release, by controlling ASK1 expression in RA FLS.

Cited by 108 publications

References 36 publications

Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

Unravelling the complexity of COPD by microRNAs: it's a small world after all

Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family

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