Essential role of ROS-mediated NFAT activation in TNF-α induction by crystalline silica exposure

Occupational exposure to crystalline silica has been associated with progressive pulmonary silicosis and lung cancer, but the underlying molecular mechanisms are not well understood. Previous studies have shown that crystalline silica exposure can generate reactive oxygen species (ROS) and induce the expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) in cells. TNF-α is believed to be critical in the development of silica-related diseases. Thus it will be of significance to understand the mechanisms of TNF-α induction by silica exposure. Given the fact that the transcription factor nuclear factor of activated T cells (NFAT) plays an important role in the regulation of TNF-α and can also be activated by ROS, in this study we investigated the potential role of ROS in silica-induced NFAT activity as well as TNF-α expression in Cl41 cells. The results showed that exposure of cells to silica led to NFAT transactivation and TNF-α induction, where superoxide anion radical (O2−·), but not H2O2, was involved. The knockdown of NFAT3 by its specific small interfering RNA significantly attenuated the silica-induced TNF-α transcription. This study demonstrated that silica was able to activate NFAT in an O2−·-dependent manner, which was required for TNF-α induction.

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Tobacco Smoke Exposure Exacerbated Crystalline Silica-Induced Lung Toxicity in Rats

Toxicological Sciences ◽

10.1093/toxsci/kfaa146 ◽

2020 ◽

Vol 178 (2) ◽

pp. 375-390 ◽

Cited By ~ 1

Author(s):

Tina M Sager ◽

Christina M Umbright ◽

Gul Mehnaz Mustafa ◽

Naveena Yanamala ◽

Howard D Leonard ◽

...

Keyword(s):

Gene Expression ◽

Tobacco Smoke ◽

Molecular Mechanisms ◽

Neutrophil Infiltration ◽

Crystalline Silica ◽

Lung Toxicity ◽

Tobacco Smoke Exposure ◽

Silica Exposure ◽

Lung Response

Abstract Smoking may modify the lung response to silica exposure including cancer and silicosis. Nevertheless, the precise role of exposure to tobacco smoke (TS) on the lung response to crystalline silica (CS) exposure and the underlying mechanisms need further clarification. The objectives of the present study were to determine the role of TS on lung response to CS exposure and the underlying mechanism(s). Male Fischer 344 rats were exposed by inhalation to air, CS (15 mg/m3, 6 h/day, 5 days), TS (80 mg/m3, 3 h/day, twice weekly, 6 months), or CS (15 mg/m3, 6 h/day, 5 days) followed by TS (80 mg/m3, 3 h/day, twice weekly, 6 months). The rats were euthanized 6 months and 3 weeks following initiation of the first exposure and the lung response was assessed. Silica exposure resulted in significant lung toxicity as evidenced by lung histological changes, enhanced neutrophil infiltration, increased lactate dehydrogenase levels, enhanced oxidant production, and increased cytokine levels. The TS exposure alone had only a minimal effect on these toxicity parameters. However, the combined exposure to TS and CS exacerbated the lung response, compared with TS or CS exposure alone. Global gene expression changes in the lungs correlated with the lung toxicity severity. Bioinformatic analysis of the gene expression data demonstrated significant enrichment in functions, pathways, and networks relevant to the response to CS exposure which correlated with the lung toxicity detected. Collectively our data demonstrated an exacerbation of CS-induced lung toxicity by TS exposure and the molecular mechanisms underlying the exacerbated toxicity.

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Paeoniflorin Antagonizes TNF-α-Induced L929 Fibroblastoma Cells Apoptosis by Inhibiting NF-κBp65 Activation

Dose-Response ◽

10.1177/1559325818774977 ◽

2018 ◽

Vol 16 (2) ◽

pp. 155932581877497 ◽

Cited By ~ 2

Author(s):

Xiaoyu Lai ◽

Jing Wei ◽

Xinghong Ding

Keyword(s):

Dependent Manner ◽

L929 Cells ◽

Tnf Α ◽

Flow Cytometry Detection ◽

Induced Apoptosis ◽

Factor Α ◽

Dose Dependent ◽

Necrosis Factor ◽

Inflammatory Effect

Paeoniflorin (PF) is one of the main pharmacodynamic components of Paeonia suffruticosa Andr, which has a significant anti-inflammatory effect on rheumatoid arthritis (RA), with a mechanism related to the tumor necrosis factor α (TNF-α). The aim of the present study was to investigate the role of PF in the apoptosis and expression of NF-κBp65 of L929 fibroblastoma cells induced by TNF-α. Our results showed that different concentrations of PF can significantly reduce the growth inhibition of L929 cells. Moreover, morphological observations, Hoechst 33342 staining, and flow cytometry detection of apoptosis showed that PF can significantly attenuate the TNF-α-induced apoptosis in a dose-dependent manner. Western blot analysis revealed that TNF-α induced the activation of NF-κBp65, whereas PF treatment had a marked dose-dependent suppression on it, which indicates that its action might be associated with inhibiting NF-κB signaling pathway. These results show that PF exerts a beneficial effect on L929 cells to prevent TNF-α-induced apoptosis and expression of NF-κBp65, which would be helpful to clarify its role in the treatment of RA.

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Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-α production in cultured macrophage cell lines

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00016.2009 ◽

2009 ◽

Vol 296 (5) ◽

pp. G1047-G1053 ◽

Cited By ~ 102

Author(s):

Zheng Shen ◽

Joanne M. Ajmo ◽

Christopher Q. Rogers ◽

Xiaomei Liang ◽

Lisa Le ◽

...

Keyword(s):

Cell Lines ◽

Proinflammatory Cytokines ◽

Molecular Mechanisms ◽

Sirtuin 1 ◽

Class Iii ◽

Macrophage Cell ◽

Tnf Α ◽

Sirt1 Inhibitor ◽

Factor Α

Dysregulation of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of alcoholic liver injury. Sirtuin 1 (SIRT1) is an NAD+-dependent class III protein deacetylase that is known to be involved in regulating production of proinflammatory cytokines including TNF-α. In the present study, we examined the role of SIRT1 signaling in TNF-α generation stimulated by either lipopolysaccharide (LPS), acetaldehyde (AcH), or acetate (two major metabolites of ethanol) in two cultured macrophage cell lines. In both rat Kupffer cell line 1 (RKC1) and murine RAW 264.7 macrophages, treatment with either LPS, AcH, or acetate caused significant decreases in SIRT1 transcription, translation, and activation, which essentially demonstrated an inverse relationship with TNF-α levels. LPS, AcH, and acetate each provoked the release of TNF-α from RKC1 cells, whereas coincubation with resveratrol (a potent SIRT1 agonist) inhibited this effect. Conversely, addition of sirtinol (a known SIRT1 inhibitor) or knocking down SIRT1 by the small silencing SIRT1 plasmid (SIRT1shRNA) augmented TNF-α release, suggesting that impairment of SIRT1 may contribute to TNF-α secretion. Further mechanistic studies revealed that inhibition of SIRT1 by LPS, AcH, or acetate was associated with a marked increase in the acetylation of the RelA/p65 subunit of nuclear transcription factor (NF-κB) and promotion of NF-κB transcriptional activity. Taken together, our findings suggest that SIRT1-NF-κB signaling is involved in regulating LPS- and metabolites-of-ethanol-mediated TNF-α production in rat Kupffer cells and in murine macrophages. Our study provides new insights into understanding the molecular mechanisms underlying the development of alcoholic steatohepatitis.

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Inflammatory cytokine TNF-α inhibits Na+–glutamine cotransport in intestinal epithelial cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2011-0488 ◽

2013 ◽

Vol 91 (4) ◽

pp. 275-284 ◽

Cited By ~ 6

Author(s):

Jamilur R. Talukder ◽

Brittney Boyd ◽

Ashley Griffin ◽

Antara Jaima ◽

Vazhaikkurichi M. Rajendran

Keyword(s):

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Kinetic Studies ◽

Dependent Manner ◽

Intestinal Epithelial ◽

Cell Integrity ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Glutamine (Gln), a preferred fuel source for enterocytes, is critical for intestinal epithelial cell integrity and barrier function. Chronic enteritis inhibits apical Na+–Gln cotransport. It is not known whether inflammatory cytokines that are secreted during inflammation inhibit Na+–Gln cotransport. Thus, this study aimed to examine whether TNF-α would affect apical Na+–Gln cotransport in intestinal epithelial cells. In this study, the presence of Na+–Gln cotransport was established by measuring Gln uptake in 10 days postconfluent IEC-6 cells grown on transwell plates. Cation, amino acid specificity, and siRNA transfection studies established that Na+–Gln cotransport is mediated via B0AT1. Immunoblotting and immunofluorescence studies established the apical membrane localization of B0AT1 in IEC-6 cells. Tumour necrosis factor α (TNF-α) inhibited Na+–Gln cotransport in a concentration- and time-dependent manner with an inhibitory concentration of 1.53 nmol·L−1. Quantitative real-time PCR and Western blot analyses indicated that TNF-α did not alter B0AT1-specific transcripts or protein expression level. Kinetic studies revealed that TNF-α inhibited Na+–Gln cotransport by reducing the affinity of the cotransporters for Gln, and this effect was antagonized by genistein. Thus, we conclude that the TNF-α inhibition of Na+–Gln cotransport occurs at the post-translational level, and that the IEC-6 cell line is an excellent system to study the role of cytokines in Na+–Gln cotransport.

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C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

Molecular and Cellular Biology ◽

10.1128/mcb.00494-15 ◽

2015 ◽

Vol 35 (19) ◽

pp. 3409-3422 ◽

Cited By ~ 7

Author(s):

Jorge Oller ◽

Arántzazu Alfranca ◽

Nerea Méndez-Barbero ◽

Silvia Villahoz ◽

Noelia Lozano-Vidal ◽

...

Keyword(s):

Transcription Factors ◽

Angiotensin Ii ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Vascular Remodeling ◽

Nuclear Translocation ◽

Dependent Manner ◽

Activated T Cells ◽

Nfat Activation ◽

Factor Α

Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to theAdamts-1promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease.

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Regulation of microRNAs in Inflammation-Associated Colorectal Cancer: A Mechanistic Approach

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200917112802 ◽

2020 ◽

Vol 20 ◽

Author(s):

Sridhar Muthusami ◽

Ilangovan Ramachandran ◽

Sneha Krishnamoorthy ◽

Yuvaraj Sambandam ◽

Satish Ramalingam ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Colorectal Carcinogenesis ◽

Model Systems ◽

Necrosis Factor Alpha ◽

Multi Stage ◽

Mechanistic Approach ◽

Tnf Α ◽

Factor Alpha

: The development of colorectal cancer (CRC) is a multi-stage process. The inflammation of the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease (CD) is often regarded as the initial trigger for the development of CRC. Many cytokines such as tumor necrosis factor alpha (TNF-α) and several interleukins (ILs) are known to exert proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers, including CRC through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown. Consolidating the published results and offering perspective solutions to circumvent CRC, the current review is focused on the role of miRNAs and their regulation in the development of CRC. We have also discussed the model systems adapted by researchers to delineate the role of miRNAs in inflammation-associated CRC.

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Molecular Mechanisms of Curcumin in Neuroinflammatory Disorders: A Mini Review of Current Evidences

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666181129103056 ◽

2019 ◽

Vol 19 (3) ◽

pp. 247-258 ◽

Cited By ~ 7

Author(s):

Mahsa Hatami ◽

Mina Abdolahi ◽

Neda Soveyd ◽

Mahmoud Djalali ◽

Mansoureh Togha ◽

...

Keyword(s):

Nitric Oxide ◽

English Language ◽

Molecular Mechanisms ◽

Randomized Clinical Trials ◽

Mitochondrial Dynamics ◽

Nuclear Factor Κb ◽

General Term ◽

Neuroinflammatory Disease ◽

Tnf Α ◽

Factor Α

Objective: Neuroinflammatory disease is a general term used to denote the progressive loss of neuronal function or structure. Many neuroinflammatory diseases, including Alzheimer’s, Parkinson’s, and multiple sclerosis (MS), occur due to neuroinflammation. Neuroinflammation increases nuclear factor-κB (NF-κB) levels, cyclooxygenase-2 enzymes and inducible nitric oxide synthase, resulting in the release of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). It could also lead to cellular deterioration and symptoms of neuroinflammatory diseases. Recent studies have suggested that curcumin (the active ingredient in turmeric) could alleviate the process of neuroinflammatory disease. Thus, the present mini-review was conducted to summarize studies regarding cellular and molecular targets of curcumin relevant to neuroinflammatory disorders. Methods: A literature search strategy was conducted for all English-language literature. Studies that assessed the various properties of curcuminoids in respect of neuroinflammatory disorders were included in this review. Results: The studies have suggested that curcuminoids have significant anti- neuroinflammatory, antioxidant and neuroprotective properties that could attenuate the development and symptom of neuroinflammatory disorders. Curcumin can alleviate neurodegeneration and neuroinflammation through multiple mechanisms, by reducing inflammatory mediators (such as TNF-α, IL-1β, nitric oxide and NF-κB gene expression), and affect mitochondrial dynamics and even epigenetic changes. Conclusion: It is a promising subject of study in the prevention and management of the neuroinflammatory disease. However, controlled, randomized clinical trials are needed to fully evaluate its clinical potential.

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Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

Molecular Psychiatry ◽

10.1038/s41380-021-01016-1 ◽

2021 ◽

Author(s):

Young-Min Han ◽

Min Sun Kim ◽

Juyeong Jo ◽

Daiha Shin ◽

Seung-Hae Kwon ◽

...

Keyword(s):

Inhibitory Action ◽

Time Course ◽

Molecular Mechanisms ◽

Late Phase ◽

Fine Tuning ◽

Dependent Manner ◽

Middle Phase ◽

Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

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Bacteriophages immunomodulate the response of monocytes

Experimental Biology and Medicine ◽

10.1177/1535370221995154 ◽

2021 ◽

pp. 153537022199515

Author(s):

Lídia Perea ◽

Lorena Rodríguez-Rubio ◽

Juan C Nieto ◽

Carlos Zamora ◽

Elisabet Cantó ◽

...

Keyword(s):

Cytokine Production ◽

Statistical Significance ◽

Control Sample ◽

Polymyxin B ◽

Dependent Manner ◽

Direct Role ◽

Gram Positive Bacteria ◽

Hla Dr ◽

Tnf Α

Bacteriophages are present in fluids from cirrhosis patients. However, their effect on the immune response is unknown. In this work, we explore the role of phages in the phenotype, function, and cytokine production of monocytes. We stimulated healthy monocytes with five different butanol-purified phage suspensions infective for Gram-negative and Gram-positive bacteria. We studied the expression of the monocyte markers involved in lipopolysaccharide recognition (LPS; CD14), antigen presentation (HLA-DR) and co-stimulation (CD86), and the concentration of induced cytokines (TNF-α, IFN-α, and IL-10) by phages. To confirm the direct role of phages without the interference of contaminating soluble LPS in phage suspensions, polymyxin B was added to the cell cultures. Phagocytosis experiments were assessed by flow cytometry using labeled phage suspensions. We observed that butanol-purified phages reduced the surface levels of CD14 and CD86 in monocytes and increased the secreted levels of TNF-α and IL-10 compared with the control sample containing only butanol buffer. All phage suspensions showed downregulation of HLA-DR expression but only Staphylococcus aureus phage contaminated with Escherichia coli reached statistical significance. The addition of polymyxin B did not restore the monocytic response induced by phages, suggesting that the effect was not caused by the presence of LPS. Monocytes were able to phagocyte phages in a dose- and time-dependent manner. To conclude, the phagocytosis of butanol-purified phages altered the phenotype and cytokine production of monocytes suggesting they become tolerogenic.

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