MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

Lai, Lihua; Song, Yinjing; Liu, Yang; Chen, Qing‐Yun; Han, Qingpeng; Chen, Weilin; Pan, Ting; Zhang, Yuanyuan; Cao, Xuetao; Wang, Qingqing

doi:10.1074/jbc.m112.445429

Cited by 117 publications

(86 citation statements)

References 65 publications

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“…39,44 The presence of somatic hypermutations would suggest a memory B cell of origin; however, absence of CD27 and somatic hypermutations in a subgroup of WM patients 6,39,45,46 would favor, at least in the latter cases, a nongerminal center cellular origin. 48,49 ), and even several genes related to cellular development, growth and proliferation, as well as genes downstream of the interferon g regulator were found to be more active in CD22 low CD25 1 B-cells compared to the Waldenström clone. Interferon g-producing B cells have been recently described as a new subset that can promote innate responses against intracellular infection, via increased Bruton tyrosine kinase signaling and NF-kB activation, after CD40 ligation.…”

Section: Discussionmentioning

confidence: 99%

The cellular origin and malignant transformation of Waldenström macroglobulinemia

Paiva

Corchete

Vidriales

et al. 2015

Blood

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Key Points• Benign (ie, IgM MGUS and smoldering WM) clonal B cells already harbor the phenotypic and molecular signatures of the malignant WM clone.• Multistep transformation from benign (ie, IgM MGUS and smoldering WM) to malignant WM may require specific copy number abnormalities.Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n 5 22), smoldering (n 5 16), and symptomatic WM (n 5 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25 2 CD22 1 B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25 1 CD221low ) B-cell counterpart. The frequency of specific copy number abnormalities [14, del(6q23.3-6q25.3), 112, and 118q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P 5 .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone. (Blood. 2015;125(15):2370-2380

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Section: Discussionmentioning

confidence: 99%

The cellular origin and malignant transformation of Waldenström macroglobulinemia

Paiva

Corchete

Vidriales

et al. 2015

Blood

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“…Ning et al [40] demonstrated a positive effect of miR-92a on the proliferation, differentiation, and survival of chondrogenic progenitor cells by targeting nog3, an inhibitor of the BMP signaling pathway. MiR-92a expression decreases rapidly in macrophages upon stimulation with Toll-like receptor ligands, and miR-92a controls the inflammatory response by targeting the MKK4/JNK/c-Jun pathway [41]. In our previous studies, we demonstrated that miR-92a-3p plays an important role in both cartilage development and degeneration via directly targeting HDAC2, and that siHDAC2 can also repress the expression of ADAMTS-4/5 in primary human chondrocytes [26,27].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1β-Induced Catabolism in Human Articular Chondrocytes

Mao¹,

Zhang²,

Zhang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) are secreted enzymes belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family that play significant roles in the progression of osteoarthritis (OA). Here, we aimed to determine whether the expression of ADAMTS-4/5 in chondrogenesis and inflammation is regulated by microRNA-92a-3p (miR-92a-3p). Methods: MiR-92a-3p and ADAMTS-4/5 expressions were determined by quantitative polymerase chain reaction (qPCR). To investigate the repressive effect of miR-92a-3p on ADAMTS-4/5 expression, chondrogenic human mesenchymal stem cells (hMSCs) and human chondrocytes were transfected with mature miR-92a-3p or an antisense inhibitor (anti-miR-92a-3p), respectively. ADAMTS-4/5 protein production was quantified by enzyme-linked immunosorbent assay (ELISA), and miR92a-3p involvement in IL-1β-mediated catabolic effects was examined by immunoblotting. The roles of activated MAP kinases (MAPK) and nuclear factor (NF)-κB were evaluated by using specific inhibitors. Interaction between miR-92a-3p and its putative binding site in the 3′-untranslated region (3′-UTR) of ADAMTS-4/5 mRNA was confirmed by luciferase reporter assay. Results: miR-92a-3p expression was elevated in chondrogenic hMSCs, with significantly lower expression in OA cartilage than in normal cartilage. Stimulation with IL-1β significantly reduced miR-92a-3p expression in primary human chondrocytes (PHCs). Transfection of chondrocytes with miR-92a-3p downregulated IL-1β-induced ADAMTS-4/5 expression, and the activity of a reporter construct containing the 3′-UTR of human ADAMTS-4/5 mRNA.

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“…miR-146a is rapidly upregulated by LPS in human monocytic cells and regulates TLR4 signaling by targeting tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase (IRAK) [12] . miR-92a negatively regulates TLR-triggered inflammatory response in macrophages by targeting mitogen-activated protein kinase kinase 4 (MKK4) [13] . miR-21 is induced via the MyD88 pathway in macrophages www.nature.com/aps Sun Y et al Acta Pharmacologica Sinica npg triggered by LPS and controls inflammation by targeting proinflammatory tumor suppressor programmed cell death 4 (PDCD4) [14] .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-124 negatively regulates LPS-induced TNF-α production in mouse macrophages by decreasing protein stability

Sun

Qin

et al. 2016

Acta Pharmacol Sin

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Aim: MicroRNAs play pivotal roles in regulation of both innate and adaptive immune responses. In the present study, we investigated the effects of microRNA-124 (miR-124) on production of the pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-treated mouse macrophages. Methods: Mouse macrophage cell line RAW264.7 was stimulated with LPS (100 ng/mL). The levels of miR-124 and TNF-α mRNA were evaluated using q-PCR. ELISA and Western blotting were used to detect TNF-α protein level in cell supernatants and cells, respectively. 3′-UTR luciferase reporter assays were used to analyze the targets of miR-124. For in vivo experiments, mice were injected with LPS (30 mg/kg, ip). Results: LPS stimulation significantly increased the mRNA level of miR-124 in RAW264.7 macrophages in vitro and mice in vivo. In RAW264.7 macrophages, knockdown of miR-124 with miR-124 inhibitor dose-dependently increased LPS-stimulated production of TNF-α protein and prolonged the half-life of TNF-α protein, but did not change TNF-α mRNA levels, whereas overexpression of miR-124 with miR-124 mimic produced the opposite effects. Furthermore, miR-124 was found to directly target two components of deubiquitinating enzymes: ubiquitin-specific proteases (USP) 2 and 14. Knockdown of USP2 or USP14 accelerated protein degradation of TNF-α, and abolished the effect of miR-124 on TNF-α protein stability. Conclusion: miR-124, targeting USP2 and USP14, negatively regulates LPS-induced TNF-α production in mouse macrophages, suggesting miR-124 as a new therapeutic target in inflammation-related diseases.

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MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

Cited by 117 publications

References 65 publications

The cellular origin and malignant transformation of Waldenström macroglobulinemia

The cellular origin and malignant transformation of Waldenström macroglobulinemia

MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1β-Induced Catabolism in Human Articular Chondrocytes

MicroRNA-124 negatively regulates LPS-induced TNF-α production in mouse macrophages by decreasing protein stability

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