scholarly journals Toxoplasma gondiiTachyzoites Inhibit Proinflammatory Cytokine Induction in Infected Macrophages by Preventing Nuclear Translocation of the Transcription Factor NF-κB

2001 ◽  
Vol 167 (4) ◽  
pp. 2193-2201 ◽  
Author(s):  
Barbara A. Butcher ◽  
Leesun Kim ◽  
Peter F. Johnson ◽  
Eric Y. Denkers
Keyword(s):  
Transcription Factor ◽  
Proinflammatory Cytokine ◽  
Nuclear Translocation ◽  
Cytokine Induction

scholarly journals RIP3 impedes transcription factor EB to suppress autophagic degradation in septic acute kidney injury

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Ruizhao Li ◽  
Xingchen Zhao ◽  
Shu Zhang ◽  
Wei Dong ◽  
Li Zhang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Kidney Injury ◽  
Septic Acute Kidney Injury ◽  
Transcription Factor Eb ◽  
Autophagic Degradation ◽  
Lps Treatment

AbstractAutophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.

scholarly journals The role of phagocytosis-dependent activation of TFEB in the clearance of salmonella

2021 ◽  
Author(s):  
Erika Ospina Escobar
Keyword(s):  
Transcription Factor ◽  
Salmonella Typhimurium ◽  
Nuclear Translocation ◽  
Steady Increase ◽  
Phagosome Maturation ◽  
Salmonella Infection ◽  
Complex Interplay ◽  
Transcription Factor Eb ◽  
Insight Into

During phagocytosis, macrophages engulf and sequester pathogens into phagosomes. Phagosomes then fuse with acidic and degradative lysosomes to degrade the internalized pathogen. We previously demonstrated that phagocytosis of IgG-opsonized particles and non-opsonized E.coli causes activation of the Transcription Factor EB (TFEB), which enhances the expression of lysosomal genes, increases the degradative capacity of lysosomes and boosts bactericidal activity. However, pathogens like Salmonella typhimurium have evolved mechanisms to evade and/or alter phagosome maturation to promote their own survival. We investigated: i) whether pathogens like Salmonella can alter TFEB activation and ii) whether phagocytosis-dependent activation of TFEB can counteract the pathogenicity of microorganisms. Here, we show that non-viable (heat-killed) S. typhimurium, pathogenic (EHEC and UPEC) and non-pathogenic E.coli (DH5α) all caused TFEB nuclear translocation in RAW macrophages, while strikingly live S. typhimurium maintained TFEB in the cytosol in the first hours post-infection. By contrast, Salmonella mutants for ΔsifA, ΔsopD2, ΔphoP all triggered TFEB activation in the first hour of infection. However, Salmonella infection eventually triggered a steady increase in nuclear TFEB after 4 h of infection, suggesting a more complex interplay between TFEB and Salmonella infection. We dissected the importance of TFEB activation towards Salmonella survivability by pre-activating TFEB before infection within WT macrophages and macrophages with a CRISPR-based deletion of TFEB. Our work suggests that Salmonella actively interferes with TFEB signaling in order to enhance its own survival. These results could provide insight into using TFEB as a target for the clearance of infections.

scholarly journals SUBCELLULAR LOCALIZATION OF FoxP3 TRANSCRIPTION FACTOR IN PATIENTS WITH ACUTE CORONARY SYNDROME: COMPARATIVE ANALYSIS AND PROSPECTIVE OBSERVATION

2021 ◽  
Vol 23 (4) ◽  
pp. 731-736
Author(s):  
I. V. Kologrivova ◽  
Tatiana E. Suslova ◽  
V. V. Ryabov ◽  
M. A. Shtatolkina ◽  
O. A. Koshelskaya ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Transcription Factor ◽  
T Lymphocytes ◽  
Subcellular Localization ◽  
Nuclear Localization ◽  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Coronary Syndrome ◽  
Treg Lymphocytes

The key cellular and molecular factors being involved in the resolution of inflammation following acute myocardial infarction remain poorly understood. T-regulatory (Treg) lymphocytes are characterized by the extreme potential to regulate the strength and direction of immune responses during the myocardial injury. The functional activity of Treg-lymphocytes depends upon the transcription factor forkhead box protein P3 (FoxP3). It may be also expressed in conventional T-lymphocytes at the stage of their activation. Nuclear localization of FoxP3 is a prerequisite factor determining its ability to impact the suppressive functions of Treglymphocytes.The aim of the present study was comparative evaluation of FoxP3+T-lymphocytes frequency and counts, combined with estimation of FoxP3 subcellular localization, in patients with acute myocardial infarction and chronic coronary syndrome and examination of changes of these parameters in the short-term follow-up of patients with myocardial infarction. The study included 14 patients with chronic coronary syndrome (8 males; 6 females; 63.2±9.0 y.o.) and 5 patients with acute anterior ST-segment elevation myocardial infarction (4 males; 1 female; 61.4±11.2 y.o.) at days 1, 3 and 7 after the event. The frequency of FoxP3+ conventional and regulatory T-lymphocytes was evaluated in peripheral blood mononuclear cells together with estimation of the level of FoxP3 nuclear localization by imaging flow cytometry.Patients with infarction were characterized by the decreased counts of FoxP3+Treg-lymphocytes compared to patients with chronic coronary syndrome, and exhibited even further decrease in the counts of FoxP3+Tregcells at day 7 after infarction, while frequency of Treg and conventional T-lymphocytes did not differ significantly. The level of FoxP3 nuclear translocation was lower both in Treg and conventional T-lymphocytes in patients at day 1 post-infarction compared to patients with chronic coronary syndrome. Absolute counts of FoxP3+Tregs with nuclear FoxP3 localization remained significantly lower both at days 1 and 7 post-infarction compared to patients with chronic coronary syndrome.Thus, here we demonstrated that FoxP3 nuclear localization experiences decrease in the course of acute myocardial infarction and may serve as a more sensitive marker of changes in Treg-lymphocyte functioning than simple evaluation of their frequency. 

Induction of HOXA3 by PRRSV inhibits IFN-I response through negatively regulation of HO-1 transcription

2021 ◽  
Author(s):  
Yingtong Feng ◽  
Xuyang Guo ◽  
Hong Tian ◽  
Yuan He ◽  
Yang Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Host Cells ◽  
Type I Interferons ◽  
Economic Losses ◽  
Heme Oxygenase 1 ◽  
Type I

Type I interferons (IFN-I) play a key role in the host defense against virus infection, but porcine reproductive and respiratory syndrome virus (PRRSV) infection does not effectively activate IFN-I response, and the underlying molecular mechanisms are poorly characterized. In this study, a novel transcription factor of the heme oxygenase-1 (HO-1) gene, homeobox A3 (HOXA3), was screened and identified. Here, we found that HOXA3 was significantly increased during PRRSV infection. We demonstrated that HOXA3 promotes PRRSV replication by negatively regulating the HO-1 gene transcription, which is achieved by regulating type I interferons (IFN-I) production. A detailed analysis showed that PRRSV exploits HOXA3 to suppress beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression in host cells. We also provide direct evidence that the activation of IFN-I by HO-1 depends on its interaction with IRF3. Then we further proved that deficiency of HOXA3 promoted the HO-1-IRF3 interaction, and subsequently enhanced IRF3 phosphorylation and nuclear translocation in PRRSV-infected cells. These data suggest that PRRSV uses HOXA3 to negatively regulate the transcription of the HO-1 gene to suppress the IFN-I response for immune evasion. IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, leads the pork industry worldwide to significant economic losses. HOXA3 is generally considered to be an important molecule in the process of body development and cell differentiation. Here, we found a novel transcription factor of the HO-1 gene, HOXA3, can negatively regulate the transcription of the HO-1 gene and play an important role in the suppression of IFN-I response by PRRSV. PRRSV induces the upregulation of HOXA3, which can negatively regulate HO-1 gene transcription, thereby weakening the interaction between HO-1 and IRF3 for inhibiting the type I IFN response. This study extends the function of HOXA3 to the virus field for the first time and provides new insights into PRRSV immune evasion mechanism.

Abstract 14078: Ros-dependent Sumoylation of Cu Chaperone Atox1 Drives Its Nuclear Translocation to Promote Inflammatory Angiogenesis Induced by Ischemic Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Archita Das ◽  
Sudhahar Varadarajan ◽  
David Fulton ◽  
Yali Hou ◽  
Xuexiu Fang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nuclear Translocation ◽  
Lysyl Oxidase ◽  
Ischemic Injury ◽  
Inflammatory Cells ◽  
Hindlimb Ischemia ◽  
Barrier Dysfunction ◽  
Oxidative Inactivation ◽  
Inflammatory Angiogenesis

Introduction: Neovascularization in response to ischemia depends on inflammation, angiogenesis and reactive oxygen species (ROS). Copper (Cu) is implicated in inflammation and angiogenesis. We reported that cytosolic Cu chaperone Atox1 activates secretory Cu enzymes lysyl oxidase (LOX), while nuclear Atox1 functions as a Cu-dependent transcription factor to promote ROS/NFkB-dependent inflammation in endothelial cells (ECs). However, mechanism of Atox1 nuclear translocation as well as role of endothelial Atox1 in inflammatory angiogenesis in vivo remain unknown. SUMOylation and its deSUMOylation by SENPs regulates transcription factor function. Silica analysis identified a conserved putative SUMOylation motif at Lys(K3) of Atox1. Results: Atox1 expression was dramatically increased in angiogenic ECs in mice hindlimb ischemia model. EC-specific Atox1-deficient mice significantly reduced angiogenesis (CD31+, 67%) and Mac+ inflammatory cells in ischemic tissues. In cultured ECs, inflammatory cytokine TNFα or hypoxia promoted Atox1 nuclear translocation and Atox1 SUMOylation (3.6-fold), which were inhibited by antioxidant NAC or overexpression of “SUMO-dead” Atox1K3R. Mechanistically, TNFα induced Cys603 oxidation/inactivation of SENP1 in cytosol, which in turn increased Atox1 SUMOylation and nuclear translocation. Functionally, siAtox1or Atox1K3R inhibited TNFα-induced inflammatory/angiogenic genes VCAM/ICAM, IL-15 and RANTES. In nucleus with reduced state, ChIP assay using SUMO-Atox1 revealed that Atox1 deSUMOylation by nuclear SENP1 increases Atox1 transcriptional activity for inflammatory genes. In parallel, Atox1K3R which maintains Cu chaperone function inhibited TNFα-induced EC permeability by activating LOX. In vivo, Atox1 SUMOylation was increased after hindlimb ischemia while CRISPR/Cas9-generated SUMO-dead Atox1K3R knock-in mice showed impaired angiogenesis in hindlimb ischemia model. Conclusion: Atox1 SUMOylation via oxidative/inactivation of SENP1 in cytosol promotes: 1) its translocation to nucleus where deSUMOylated Atox1 can function as Cu-dependent transcription factor to drive inflammatory angiogenesis and 2) EC barrier dysfunction in inflamed/hypoxic ECs after ischemic injury.

scholarly journals Cisplatin-mediated activation of glucocorticoid receptor induces platinum resistance via MAST1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chaoyun Pan ◽  
JiHoon Kang ◽  
Jung Seok Hwang ◽  
Jie Li ◽  
Austin C. Boese ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Tumor Growth ◽  
Nuclear Translocation ◽  
Mapk Pathway ◽  
Underlying Mechanism ◽  
Patient Treatment ◽  
Platinum Resistance ◽  
Platinum Based Chemotherapy

AbstractAgonists of glucocorticoid receptor (GR) are frequently given to cancer patients with platinum-containing chemotherapy to reduce inflammation, but how GR influences tumor growth in response to platinum-based chemotherapy such as cisplatin through inflammation-independent signaling remains largely unclear. Combined genomics and transcription factor profiling reveal that MAST1, a critical platinum resistance factor that reprograms the MAPK pathway, is upregulated upon cisplatin exposure through activated transcription factor GR. Mechanistically, cisplatin binds to C622 in GR and recruits GR to the nucleus for its activation, which induces MAST1 expression and consequently reactivates MEK signaling. GR nuclear translocation and MAST1 upregulation coordinately occur in patient tumors collected after platinum treatment, and align with patient treatment resistance. Co-treatment with dexamethasone and cisplatin restores cisplatin-resistant tumor growth, whereas addition of the MAST1 inhibitor lestaurtinib abrogates tumor growth while preserving the inhibitory effect of dexamethasone on inflammation in vivo. These findings not only provide insights into the underlying mechanism of GR in cisplatin resistance but also offer an effective alternative therapeutic strategy to improve the clinical outcome of patients receiving platinum-based chemotherapy with GR agonists.

scholarly journals Suppression of LPS-Induced Inflammation by Chalcone Flavokawain A through Activation of Nrf2/ARE-Mediated Antioxidant Genes and Inhibition of ROS/NFκB Signaling Pathways in Primary Splenocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Hsin-Ling Yang ◽  
Ting-Yu Yang ◽  
Yugandhar Vudhya Gowrisankar ◽  
Chun-Huei Liao ◽  
Jiunn-Wang Liao ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Ex Vivo ◽  
Root Extract ◽  
Piper Methysticum ◽  
Serum Lipase ◽  
Antioxidant Genes ◽  
Anti Inflammatory

Oxidative stress is an important contributing factor for inflammation. Piper methysticum, also known as Kava-kava, is a shrub whose root extract has been consumed as a drink by the pacific islanders for a long time. Flavokawain A (FKA) is a novel chalcone derived from the kava plant that is known to have medicinal properties. This study was aimed at demonstrating the antioxidant molecular mechanisms mediated by FKA on lipopolysaccharide- (LPS-) induced inflammation in BALB/c mouse-derived primary splenocytes. In vitro data show that the nontoxic concentrations of FKA (2-30 μM) significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) release but induced the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine. It was also shown that FKA pretreatment significantly downregulated the LPS-induced ROS production and blocked the activation of the NFκB (p65) pathway leading to the significant suppression of iNOS, COX-2, TNF-α, and IL-1β protein expressions. Notably, FKA favored the nuclear translocation of Nrf2 leading to the downstream expression of antioxidant proteins HO-1, NQO-1, and γ-GCLC via the Nrf2/ARE signaling pathway signifying the FKA’s potent antioxidant mechanism in these cells. Supporting the in vitro data, the ex vivo data obtained from primary splenocytes derived from the FKA-preadministered BALB/c mice (orally) show that FKA significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) secretion in control-, LPS-, or Concanavalin A- (Con A-) stimulated cells. A significant decrease in the ratios of pro- and anti-inflammatory cytokines (IL-6/IL-10; TNF-α/IL-10) showed that FKA possesses strong anti-inflammatory properties. Furthermore, BALB/c mice induced with experimental pancreatitis using cholecystokinin- (CCK-) 8 showed decreased serum lipase levels due to FKA pretreatment. We conclude that with its potent antioxidant and anti-inflammatory properties, chalcone flavokawain A could be a novel therapeutic agent in the treatment of inflammation-associated diseases.

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