scholarly journals Effect of TNFAIP8 on the immune function of Th17 cells via p53/ p21/ MDM2 pathway after acute insult

2021 ◽  
Author(s):  
Xiaobin Cheng ◽  
Min Wang ◽  
Jing Li ◽  
Gang Li
Keyword(s):  
Cell Proliferation ◽  
Immune Function ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Immune Cell ◽  
P53 Protein ◽  
Cecal Ligation ◽  
Flow Cytometric Analysis ◽  
Male Adult ◽  
Acute Insult

Abstract Background: Th17 cells induced immunosuppression plays a vital role during sepsis. Belonging to the tumor necrosis factor α induced protein 8 (TNFAIP8) family, TNFAIP8 associates with different immune cell physiopathological processes, thus its underlying regulatory mechanisms on Th17 cells in the acute insult processes have not been fully elucidated. Result: Sepsis was induced by cecal ligation and puncture (CLP) in the male adult C57BL/6 mice. The stable TNFAIP8 knockdown Th17 cells were established via lentiviral transfection with TNFAIP8-specific SiRNA . CCK-8 assay was conducted for measuring Th17 cell proliferation. Flow cytometric analysis was adopted for examining by flow cytometry. The p53/ p21/ MDM2 pathway was measured through western blot. As a result, high TNFAIP8 expression was related with acute insult and survival rate in septic mice. TNFAIP8 SiRNA reduced Th17 cell proliferation as well as cytokines production in vivo and in vitro. In addition, TNFAIP8 KD increased the Th17 cells apoptosis in WT and septic mice. Further, TNFAIP8 influences immune function of Th17 cell involving the p53/ p21/ MDM2 signaling. Actually, TNFAIP8 KD was suggested to regulate the up-regulation of P21 and MDM2, thereby increasing p53 protein expression during sepsis. P53 gene silencing contributed to reversing cell proliferation and apoptosis regulated by TNFAIP8 KD. Conclusion: Our work concluded that TNFAIP8 affected the immune function of Th17 cells, which is mediated via the p53/ p21/ MDM2 pathway after acute insult.

Functional analysis of two STAT1 gain-of-function mutations in two Iranian families with autosomal dominant chronic mucocutaneous candidiasis

2020 ◽  
Author(s):  
Vajiheh Ostadi ◽  
Roya Sherkat ◽  
Melanie Migaud ◽  
Seyed-Mehran Modaressadeghi ◽  
Jean-Laurent Casanova ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
T Cell Proliferation ◽  
Chronic Mucocutaneous Candidiasis ◽  
Healthy Controls ◽  
Mucocutaneous Candidiasis ◽  
Ifn Γ

Abstract Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients’ peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients’ PBMCs upon interferon (IFN)-γ stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-γ. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.

scholarly journals Metabolic and Epigenomic Regulation of Th17/Treg Balance by the Polyamine Pathway

2020 ◽  
Author(s):  
Chao Wang ◽  
Allon Wagner ◽  
Johannes Fessler ◽  
Julian Avila-Pacheco ◽  
Jim Karminski ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Metabolic Flux ◽  
Cell Function ◽  
Immune Cell ◽  
Disease Model ◽  
Epigenomic Regulation ◽  
Dramatic Shift ◽  
Cell Effector

ABSTRACTCellular metabolism can orchestrate immune cell function. We previously demonstrated that lipid biosynthesis represents one such gatekeeper to Th17 cell functional state. Utilizing Compass, a transcriptome-based algorithm for prediction of metabolic flux, we constructed a comprehensive metabolic circuitry for Th17 cell function and identified the polyamine pathway as a candidate metabolic node, the flux of which regulates the inflammatory function of T cells. Testing this prediction, we found that expression and activities of enzymes of the polyamine pathway were enhanced in pathogenic Th17 cells and suppressed in regulatory T cells. Perturbation of the polyamine pathway in Th17 cells suppressed canonical Th17 cell cytokines and promoted the expression of Foxp3, accompanied by dramatic shift in transcriptome and epigenome, transitioning Th17 cells into a Treg-like state. Genetic and chemical perturbation of the polyamine pathway resulted in attenuation of tissue inflammation in an autoimmune disease model of central nervous system, with changes in T cell effector phenotype.

Inhibition of Proliferation and Induction of Apoptosis by Thymoquinone via Modulation of TGF Family, p53, p21 and Bcl-2α in Leukemic Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 210-215 ◽  
Author(s):  
Mona Diab-Assaf ◽  
Josiane Semaan ◽  
Marwan El-Sabban ◽  
Soad K. Al Jaouni ◽  
Rania Azar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Flow Cytometric Analysis ◽  
Leukemic Cells ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Apoptosis Induction ◽  
Inhibition Of Proliferation ◽  
Human T Cell

Introduction: Adult T-cell leukemia (ATL) is an aggressive form of malignancy caused by human T- cell lymphotropic virus 1 (HTLV-1). Currently, there is no effective treatment for ATL. Thymoquinone has been reported to have anti-cancer properties. Objective: The aim of this study is to investigatthe effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. Materials and Methods: Cells were incubated with different thymoquinone concentrations for 24h. Cell cytotoxicity was assayed using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96® Non-Radioactive Cell Proliferation. Cell cycle analysis was performed by staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. Results: At non-cytotoxic concentrations of TQ, it resulted in the inhibition of proliferation in a dose dependent manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increase DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFβ1, p53 and p21 and a down-regulation of TGF-α and Bcl-2α. Conclusion: Thymoquinone presents antiproliferative and proapoptotic effects in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL.

Evidence for Associations Between Th1/Th17 “Hybrid” Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy

2020 ◽  
Vol 105 (6) ◽  
pp. 1851-1867 ◽  
Author(s):  
Sijie Fang ◽  
Shuo Zhang ◽  
Yazhuo Huang ◽  
Yu Wu ◽  
Yi Lu ◽  
...  
Keyword(s):  
T Cell ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Cell Subsets ◽  
Th1 Cell ◽  
Effector T Cell ◽  
Cell Lineages ◽  
Graves Orbitopathy ◽  
Ifn Γ

Abstract Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

scholarly journals Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

2021 ◽  
Vol 38 (2) ◽  
Author(s):  
Wenqian Zheng ◽  
Jinhui Hu ◽  
Yiming Lv ◽  
Bingjun Bai ◽  
Lina Shan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Dependent Signaling Pathway ◽  
Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

scholarly journals Generation of IL-8 and IL-9 Producing CD4+T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Michaela Gasch ◽  
Tina Goroll ◽  
Mario Bauer ◽  
Denise Hinz ◽  
Nicole Schütze ◽  
...  
Keyword(s):  
T Cells ◽  
T Helper Cells ◽  
Th17 Cells ◽  
Immune Cell ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Helper Cells ◽  
Aryl Hydrocarbon

The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells underin vitroconditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

Flow cytometric analysis of T cell proliferation in a mixed lymphocyte reaction with dendritic cells

2003 ◽  
Vol 275 (1-2) ◽  
pp. 57-68 ◽  
Author(s):  
Xuan Duc Nguyen ◽  
Hermann Eichler ◽  
Alex Dugrillon ◽  
Christoph Piechaczek ◽  
Michael Braun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
Mixed Lymphocyte Reaction ◽  
Flow Cytometric Analysis ◽  
T Cell Proliferation ◽  
Flow Cytometric

Abstract MP50: Time Restricted Feeding Reduces Interleukin 17a Production Associated With Western Diets

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Gwendolyn K Davis ◽  
Daniel Fehrenbach ◽  
Charles D Smart ◽  
Claudia Edell ◽  
Jennifer Pollock ◽  
...  
Keyword(s):  
T Cell ◽  
Circadian Rhythms ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Fold Increase ◽  
Organ Damage ◽  
High Salt ◽  
Restricted Feeding ◽  
High Fat ◽  
Interleukin 17A

Circadian rhythms govern our daily physiological processes. However, disruption of circadian rhythms, as can occur with ad libitum Western diets, disrupt these processes leading to cardiometabolic diseases. Our lab and others have shown that Th17 cells, which produce interleukin 17A (IL-17A), are implicated in the development of cardiovascular and renal end-organ damage associated with high fat and/or high salt diets. Th17 cell differentiation and trafficking is regulated by the circadian clock and influenced by light-dark cycles. However, whether feeding-fasting rhythms influence Th17 cell responses is poorly understood. We tested the hypothesis that limiting food intake to the 12-hr active period (time-restricted feeding, TRF) mitigates high fat and high salt (HF/HS) diet induced T cell IL-17A production and target organ damage. Beginning at 8 weeks of age, male C57Bl/6J mice were placed on either a normal chow/normal salt (NC/NS) or a HF/HS diet for 20 weeks, with TRF intervention occurring during the last two weeks in the HF/HS + TRF group. Body weight was similarly significantly increased in the HF/HS and HF/HS + TRF groups in comparison to the NC/NS group. Th17 cells were significantly increased (2.6-fold increase, p = 0.02) in the Peyer’s patches (lymphoid aggregates found in the small intestines) of mice on HF/HS diet in comparison to those on NC/NS. Importantly, TRF abolished this increase. Renal CD4 + T cell IL-17A production, as measured by flow cytometry, was increased by HF/HS diet compared to NC/NS (3-fold increase, p = 0.02). Similarly, TRF abolished this increase. This study highlights how Western diets exacerbate intestinal and renal IL-17A production and the potential beneficial impact of a behavioral intervention, TRF, to mitigate the Th17 mediated inflammation associated with diet-induced obesity.

scholarly journals Pentoxifylline prevents the transition from the hyperdynamic to hypodynamic response during sepsis

1999 ◽  
Vol 277 (3) ◽  
pp. H1036-H1044 ◽  
Author(s):  
Shaolong Yang ◽  
Mian Zhou ◽  
Douglas J. Koo ◽  
Irshad H. Chaudry ◽  
Ping Wang
Keyword(s):  
Blood Flow ◽  
Cardiac Output ◽  
Cardiovascular Response ◽  
Cecal Ligation ◽  
Organ Blood Flow ◽  
Adult Rats ◽  
Male Adult ◽  
Morphological Alterations ◽  
Beneficial Effects ◽  
Renal Oxygen

The cardiovascular response to sepsis includes an early, hyperdynamic phase followed by a late, hypodynamic phase. Although administration of pentoxifylline (PTX) produces beneficial effects in sepsis, it remains unknown whether this agent prevents the transition from the hyperdynamic to the hypodynamic response during the progression of sepsis. To study this, male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). At 1 h after CLP, PTX (50 mg/kg body wt) or vehicle was infused intravenously over 30 min. At 20 h after CLP (i.e., the late stage of sepsis), cardiac output and organ blood flow were measured by radioactive microspheres. Systemic and regional (i.e., hepatic, intestinal, and renal) oxygen delivery (Do 2) and oxygen consumption (V˙o 2) were determined. Moreover, plasma levels of lactate and alanine aminotransferase (ALT) were measured, and histological examinations were performed. In additional animals, the necrotic cecum was excised at 20 h after CLP, and mortality was monitored for 10 days thereafter. The results indicate that cardiac output, organ blood flow, and systemic and regional Do 2decreased by 36–65% ( P < 0.05) at 20 h after CLP. Administration of PTX early after the onset of sepsis, however, prevented reduction in measured hemodynamic parameters and increased systemic and regional Do 2 andV˙o 2 by 50–264% ( P < 0.05). The elevated levels of lactate (by 173%, P < 0.05) and ALT (by 718%, P < 0.05), as well as the morphological alterations in the liver, small intestine, and kidneys during sepsis were attenuated by PTX treatment. In addition, PTX treatment decreased the mortality rate from 50 to 0% ( P < 0.05) after CLP and cecal excision. Because PTX prevents the occurrence of hypodynamic sepsis, this agent appears to be a useful adjunct for maintaining hemodynamic stability and preventing lethality from sepsis.

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