Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

Ren, Deshan; Liu, Fei; Dong, Guanjun; You, Ming; Ji, Jianjian; Huang, Yue; Hou, Yayi; Fan, Hong

doi:10.1038/cmi.2015.48

Cited by 23 publications

(21 citation statements)

References 49 publications

(67 reference statements)

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“…Recently, our colleagues demonstrated that mice undergoing long-term exposure to imiquimod (a TLR7 agonist) developed lupuslike symptoms. 58 Notably, these mice also showed decreased CD180 expression on B cells (data not shown), which is consistent with our current study. In SLE B cells, activation of TLR7 and TLR9 signaling is not only responsible for autoantibody production 3 but also affects B cell function by up-or downregulating the expression of various genes.…”

Section: Discussionsupporting

confidence: 82%

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

You

Dong

et al. 2015

Cell Mol Immunol

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A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-a (IFN-a) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-a signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-a signaling in B cells. We found that the number of CD180-negative B cells was increased in MRL/Mp-Fas(lpr/lpr) lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138 1 plasmablast/plasma cells and GL-7 1 germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-a-induced phosphorylation of signal transducer and activator of transcription 2 (STAT-2) and expression of IFN-stimulated genes (ISGs) in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-a-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of IFN-a signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-a signaling in SLE. Our data provide molecular insight into the mechanism of IFN-a signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment. Cellular & Molecular Immunology

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Section: Discussionsupporting

confidence: 82%

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

You

Dong

et al. 2015

Cell Mol Immunol

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“…In humans, miR-15a-3p and miR-16-1-3p are members of the miR-15 miRNA cluster located at 13q14.3 41. Dynamic regulation of the expression of members of miR-15 cluster miRNAs is associated with B-cell development 41 in chronic lymphocytic leukemia (CLL), deletion of the normal allele 42, multidrug resistance in human GC cells 43 and B-cell abnormality in systemic lupus erythematosus (SLE) 44. Ectopic expression of miR-15a and miR-16-1 suppressed gastric cancer cell proliferation by targeting YAP1 protein expression to exert tumor suppressor function in gastric adenocarcinoma 45.…”

Section: Discussionmentioning

confidence: 99%

miR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis

Wang¹,

Hou²,

Li³

et al. 2017

Int. J. Biol. Sci.

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MicroRNAs are a novel class of gene regulators that function as oncogenes or tumor suppressors. In our current study, we investigated the role of miR-15a-3p and miR-16-1-3p in the regulation of Twist1 expression and EMT process. Our bioinformatics analysis suggested that on the 3' UTR of Twist1, there are two conserved miRNA recognition sites for miR-15a-3p and miR-16-1-3p respectively. Interestingly, overexpression of miR-15a-3p and miR-16-1-3p significantly suppressed the activity of luciferase reporter containing Twist1-3' UTR, reduced mRNA and protein level of EMT related genes such as TWIST1, N-cadherin, α-SMA and Fibronectin, and repressed MMP9 and MMP2 activity, as well as cell migration and invasion. Conversely, inhibition of miR-15a-3p and miR-16-1-3p significantly increased TWIST1, N-cadherin, α-SMA and Fibronectin protein expression. In addition, Twist1 co-transfection significantly ameliorated the loss of cell migration and invasion. Moreover, overexpression of miR-15a-3p and miR-16-1-3p dramatically suppressed the ability of BGC823 cells to form colonies in vitro and develop tumors in vivo in nude mice. Finally, qPCR and Western blot analysis showed that miR-15a-3p and miR-16-1-3p were significantly reduced in clinical gastric cancer tissue, whereas Twist1 mRNA and protein were significantly up-regulated, suggesting that this aberrant down-regulation of miR-15a-3p and miR-16-1-3p might be associated with the abnormal regulation of Twist1 and the EMT process in gastric cancer development. Our results help to elucidate a novel and important mechanism for the regulation of Twist1 in the development of cancer.

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“…Recently, cyclinD3 (CCND3) was suggested to play an important role in B cell proliferation, development, and differentiation. The activation of TLR7 increased CCND3 expression via the downregulation of miR-15b in B cells [ 177 ].…”

Section: Microrna Regulating Adaptive Immunity Involved In Developmentioning

confidence: 99%

The Involvement of MicroRNAs in Modulation of Innate and Adaptive Immunity in Systemic Lupus Erythematosus and Lupus Nephritis

Honarpisheh

Köhler

Rauchhaupt

et al. 2018

Journal of Immunology Research

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Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), represent a family of RNA molecules that do not translate into protein. Nevertheless, they have the ability to regulate gene expression and play an essential role in immune cell differentiation and function. MicroRNAs were found to be differentially expressed in various tissues, and changes in their expression have been associated with several pathological processes. Yet, their roles in systemic lupus erythematosus (SLE) and lupus nephritis (LN) remain to be elucidated. Both SLE and LN are characterized by a complex dysfunction of the innate and adaptive immunity. Recently, significant findings have been made in understanding SLE through the use of genetic variant identification and expression pattern analysis and mouse models, as well as epigenetic analyses. Abnormalities in immune cell responses, cytokine and chemokine production, cell activation, and apoptosis have been linked to a unique expression pattern of a number of miRNAs that have been implicated in the immune pathogenesis of this autoimmune disease. The recent evidence that significantly increased the understanding of the pathogenesis of SLE drives a renewed interest in efficient therapy targets. This review aims at providing an overview of the current state of research on the expression and role of miRNAs in the immune pathogenesis of SLE and LN.

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Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

Cited by 23 publications

References 49 publications

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

miR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis

The Involvement of MicroRNAs in Modulation of Innate and Adaptive Immunity in Systemic Lupus Erythematosus and Lupus Nephritis

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