Downregulation of miR-633 activated AKT/mTOR pathway by targeting AKT1 in lupus CD4+ T cells

Background Accumulating evidence suggests that the AKT/mTOR pathway plays an important role in the pathogenesis of systemic lupus erythematosus (SLE) through activating T cells, and there are few studies looking into the role of microRNA (miRNAs) in the mechanism. We first found that miR-633 expression in CD4+T cells of SLE patients was significantly reduced. Objective To investigate the role of miR-633 in the AKT/mTOR pathway in lupus CD4+T cells. Methods Samples of 17 SLE cases and 16 healthy controls were collected to detect the expression of miR-633, AKT1, mTOR mRNA and proteins by quantitative polymerase chain reaction (qPCR) and Western-blot, respectively. To determine whether AKT1 is a direct target of miR-633, a luciferase assay was performed. In vitro, AKT1 siRNA, miR-633 mimics/inhibitors or negative controls were transfected to Jurkat cells, human primary CD4+T cells and lupus CD4+T cells. RNA and proteins were extracted after 48 h, and levels of AKT/mTOR pathway markers and downstream multiple cytokines were detected by qPCR or Western-blot. Results In SLE patients, the miR-633 levels in CD4+T cells were significantly decreased and negatively correlated with SLEDAI. AKT1, mTOR mRNA and proteins were all up-regulated. The degree of downregulation of miR-633 was correlated negatively with AKT1 mRNA. The luciferase assay proved that AKT1 is a direct target of miR-633. In Jurkat and lupus CD4+T cells, overexpression of miR-633 could result in lower levels of AKT1 and mTOR. Inhibition of miR-633 expression in primary CD4+T cells caused reverse effects, and protein levels of p-AKT, p-mTOR, and p-S6RP increased. Moreover, among various cytokines, the expression of IL-4, IL-17, and IFN-γ mRNA was raised. Conclusion Our study suggests that miR-633 deletion can activate the AKT/mTOR pathway by targeting AKT1 to participate in the pathogenesis of SLE.

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Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22105207 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5207

Author(s):

Chi Yan ◽

Jinming Yang ◽

Nabil Saleh ◽

Sheau-Chiann Chen ◽

Gregory D. Ayers ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Growth ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mtor Pathway ◽

Complete Regression ◽

Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607101113 ◽

2016 ◽

Vol 113 (38) ◽

pp. 10637-10642 ◽

Cited By ~ 45

Author(s):

Elaine V. Lourenço ◽

Aijing Liu ◽

Giuseppe Matarese ◽

Antonio La Cava

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

New Zealand ◽

Renal Disease ◽

Lupus Erythematosus ◽

Cellular Level ◽

Presentation Of Self ◽

Systemic Lupus ◽

Autoantibody Production

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

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MiR-410 Down-Regulates the Expression of Interleukin-10 by Targeting STAT3 in the Pathogenesis of Systemic Lupus Erythematosus

Cellular Physiology and Biochemistry ◽

10.1159/000445625 ◽

2016 ◽

Vol 39 (1) ◽

pp. 303-315 ◽

Cited By ~ 23

Author(s):

Dongmei Liu ◽

Na Zhang ◽

Xiaomei Zhang ◽

Muting Qin ◽

Youdan Dong ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Lupus Erythematosus ◽

Autoimmune Disorder ◽

Interleukin 10 ◽

Luciferase Assay ◽

Mrna Levels ◽

Healthy Controls ◽

Systemic Lupus ◽

Targeting Effect

Background/Aims: Systemic lupus erythematosus (SLE) is a heterogeneous chronic inflammatory autoimmune disorder, in the pathogenesis of which miRNAs play a versatile function. The purpose of this study was to investigate the effect of miRNA-410 on the pathogenesis of SLE in T cells of SLE patients. Methods: Real-time PCR was used to test the mRNA levels of miRNA-410 in SLE patients and healthy controls. ELISA analysis was performed to examine the production levels of IL-10. Luciferase Assay was used to confirm the targeting effect of miRNA-410 on 3'UTR of STAT3 mRNA. Results: We found that the expression level of miR-410 in T cells of SLE patients was decreased comparing to that in healthy controls, whereas overexpression of miR-410 significantly reduced the expression levels of IL-10. Furthermore, miR-410 suppresses the transcription activity of STAT3 by binding directly to the 3 'UTR of STAT3 mRNA. Moreover, silence of STAT3 down regulated IL-10 expression in CD3+ T cells. Conclusion: Our results demonstrate that miR-410 is the key regulatory factor in the pathogenesis of SLE by regulating the expression of IL-10 through targeting STAT3. These data suggest a novel function of miR-410 and bring new insight into understanding the complex mechanisms involved in SLE.

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The Role ofγδT Cells in Systemic Lupus Erythematosus

Journal of Immunology Research ◽

10.1155/2016/2932531 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Meng Wu ◽

Jinhua Yang ◽

Xiaofeng Li ◽

Junwei Chen

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Autoimmune Disease ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Multiple Organs ◽

Minor Population ◽

Neuronal Tissues ◽

A Minor

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the overproduction of autoantibodies against an array of nuclear and cytoplasmic antigens and affects multiple organs, such as the skin, joints, kidneys, and neuronal tissues. T cells have been recognized as important players in the development of SLE due to their functions in cytokine secretion, antigen presentation, and supporting B cells for antibody production.γδT cells are a minor population of T cells that play important roles in infection and tumor-associated disease. In recent years, the role ofγδT cells in autoimmune diseases has been investigated. In this review, we discussed the role ofγδT cells in the pathogenesis of SLE.

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Immunosenescence: a key player in cancer development

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00986-z ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Jingyao Lian ◽

Ying Yue ◽

Weina Yu ◽

Yi Zhang

Keyword(s):

T Cells ◽

Cytotoxic T Lymphocyte ◽

Malignant Tumors ◽

Killer Cell ◽

Antibody Therapy ◽

The Elderly ◽

Mtor Inhibition ◽

Interleukin 7 ◽

The Many

Abstract Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.

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Regulatory T cells in systemic lupus erythematosus (SLE); Role of peptide tolerance

Autoimmunity Reviews ◽

10.1016/j.autrev.2011.09.008 ◽

2012 ◽

Vol 11 (9) ◽

pp. 611-614 ◽

Cited By ~ 28

Author(s):

Priya Sawla ◽

Awlad Hossain ◽

Bevra H. Hahn ◽

Ram P. Singh

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Regulatory T Cells ◽

Lupus Erythematosus ◽

Systemic Lupus

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Acupuncture May Exert Its Therapeutic Effect through MicroRNA-339/Sirt2/NFκB/FOXO1 Axis

BioMed Research International ◽

10.1155/2015/249013 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Jia-You Wang ◽

Hui Li ◽

Chun-Mei Ma ◽

Jia-Lu Wang ◽

Xin-Sheng Lai ◽

...

Keyword(s):

Acupuncture Therapy ◽

Critical Role ◽

Luciferase Assay ◽

Cellular Functions ◽

Physiological Level ◽

Forkhead Box ◽

Bioinformatics Study ◽

Direct Target ◽

Future Work

Recently, we have found that a number of microRNAs (miRNAs) and proteins are involved in the response to acupuncture therapy in hypertensive rats. Our bioinformatics study suggests an association between these miRNAs and proteins, which include miR-339 and sirtuin 2 (Sirt2). In this paper, we aimed to investigate whether Sirt2 was a direct target of miR-339 in neurons. In human SH-SY5Y cells, the luciferase assay implied that Sirt2 was likely a target of miRNA-339. Overexpression of miR-339 downregulated Sirt2 expression, while knockdown of miR-339 upregulated Sirt2 expression in human SH-SY5Y cells and rat PC12 cells. In addition, overexpression of miR-399 increased the acetylation of nuclear factor-κB (NF-κB) and forkhead box protein O1 (FOXO1) in SH-SY5Y cells, which are known targets of Sirt2. Our findings demonstrate that miR-339 regulates Sirt2 in human and rat neurons. Since Sirt2 plays a critical role in multiple important cellular functions, our data imply that acupuncture may act through epigenetic changes and subsequent action on their targets, such as miRNA-339/Sirt2/NF-κB/FOXO1 axis. Some physiological level changes of neurons after altering the miR-339 levels are needed to validate the suggested therapeutic role of miR-339/Sirt2/NF-κB/FOXO1 axis in response to acupuncture therapy in the future work.

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