Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

Choudhury, Sumana; Gupta, P. C. Sen; Ghosh, Sayan; Mukherjee, Sudeshna; Chakraborty, Priyanka; Chatterji, Urmi; Chattopadhyay, Sreya

doi:10.1016/j.tox.2016.06.005

Cited by 31 publications

(20 citation statements)

References 52 publications

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“…35 These mechanisms have also been linked to arsenic exposure. 36–38 Cystic fibrosis and arsenic have both shown to be associated with bronchiectasis, a rare lung disease, 6,39 suggesting that arsenic may act through similar mechanisms. Cystic fibrosis is an autosomal recessive genetic lung disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene.…”

Section: Discussionmentioning

confidence: 99%

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

Sanchez

Powers

Perzanowski

et al. 2018

Curr Envir Health Rpt

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Purpose of review: Hundreds of millions of people worldwide are exposed to arsenic via contaminated water. The goal of this study was to identify whether arsenic-associated lung function deficits resemble obstructive- or restrictive-like lung disease, in order to help illuminate a mechanistic pathway and identify at-risk populations. Recent findings: We recently published a qualitative systematic review outlining the body of research on arsenic and non-malignant respiratory outcomes. Evidence from several populations, at different life stages, and at different levels of exposure showed consistent associations of arsenic exposure with chronic lung disease mortality, respiratory symptoms, and lower lung function levels. The published review, however, only conducted a broad qualitative description of the published studies without considering specific spirometry patterns, without conducting a meta-analysis, and without evaluating the dose-response relationship. Summary: We searched PubMed and Embase for studies on environmental arsenic exposure and lung function. We performed a meta-analysis using inverse-variance weighted random-effects models to summarize adjusted effect estimates for arsenic and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Across nine studies, median water arsenic levels ranged from 23 to 860 μg/L. The pooled estimated mean difference (MD) comparing the highest category of arsenic exposure (ranging from >11 to >800 μg/L) versus the lowest (ranging from <10 to <100 μg/L) for each study for FEV1 was −42 (95% confidence interval (CI): −70, −16) mL and for FVC was −50 (95%CI: −63, −37) mL. Three studies reported effect estimates for FEV1/FVC, for which there was no evidence of an association; the pooled estimated MD was 0.01 (95%CI: −0.005, 0.024). This review supports that arsenic is associated with restrictive impairments based on inverse associations between arsenic and FEV1 and FVC, but not with FEV1/FVC. Future studies should confirm whether low-level arsenic exposure is a restrictive lung disease risk factor in order to identify at-risk populations in the US.

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Section: Discussionmentioning

confidence: 99%

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

Sanchez

Powers

Perzanowski

et al. 2018

Curr Envir Health Rpt

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“…At the end of each week of treatment (LPS or fluoxetine), the behavioral tests were performed and then the hippocampus was dissected from the mice after sacrifice in sterile conditions and homogenized in 1 mL of mobile phase using a homogenizer (REMI, Mumbai, India), as explained previously . The samples were run against dopamine and serotonin (5‐HT) standards, which were purchased from Sigma Aldrich.…”

Section: Methodsmentioning

confidence: 99%

“…The samples were run against dopamine and serotonin (5‐HT) standards, which were purchased from Sigma Aldrich. The HPLC was conducted at a flow rate of 0.5 mL min −1 and the monoamine and metabolite content was determined using an electrochemical detector supplied with the instrument following a previously published method …”

Section: Methodsmentioning

confidence: 99%

“…51 HPLC At the end of each week of treatment (LPS or fluoxetine), the behavioral tests were performed and then the hippocampus was dissected from the mice after sacrifice in sterile conditions and homogenized in 1 mL of mobile phase using a homogenizer (REMI, Mumbai, India), as explained previously. 52,53 The samples were run against dopamine and serotonin (5-HT) standards, which were purchased from Sigma Aldrich. The HPLC was conducted at a flow rate of 0.5 mL min À1 and the monoamine and metabolite content was determined using an electrochemical detector supplied with the instrument following a previously published method.…”

Section: Annexin-pi Assaymentioning

confidence: 99%

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Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

et al. 2019

Self Cite

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Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti‐inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation‐induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki‐67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB‐p65 nuclear translocation. The Ki‐67high thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS‐induced proliferative conditions, thereby blocking p53‐dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation‐dictated Ki‐67high thymocytes possibly by modulating the hypothalamus–pituitary–adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation‐biased immune cells, authenticating a novel antiproliferative role of an established drug.

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“…Interestingly, sustained overproduction of IL-6/STAT3 was found to be contributed to arsenic-induced cellular transformation and carcinogenesis 7,17 . Unlike STAT3, arsenic related upregulation of NF-κB is closely correlated with increased immune-suppression instead of IL-6 upregulation response related cellular transformation 18 . Thus, the mechanisms by which miR-301a modulating STAT3 signaling in the development of arsenic-induced cellular transformation are needed to clarify.…”

Section: Introductionmentioning

confidence: 99%

Malignant Transformation of Human Bronchial Epithelial Cells Induced by Arsenic through STAT3/miR-301a/SMAD4 Loop

Zhong

Huang

Wang

et al. 2018

Sci Rep

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Arsenic is a well-known of human carcinogen and miR-301a is an oncogenic microRNA, which links to oncogenesis, however, little is understood about its contribution to arsenic-induced cellular transformation and tumorigenesis. Here, we investigated the role of miR-301a during arsenic-induced cellular transformation and tumor formation. miR-301a was found to be upregulated during arsenic-induced BEAS-2B transformation and the overexpression of miR-301a was dependent on IL-6/STAT3 signaling. Inhibition of miR-301a leads to reduction of cell proliferation, colony formation and cell migration. By using dual luciferase assay, SMAD4 was confirmed to be a direct target of miR-301a in BEAS-2B cells and upregulation of SMAD4 is involved the restraining cell growth and migration. In addition, reducing of miR-301a expression enhances doxorubicin-induced cellular apoptosis of transformed BEAS-2B through up-regulating SMAD4. Furthermore, we demonstrated that downregulation of miR-301a in BEAS-2B attenuates tumor growth in the xenograft model by targeting SMAD4. Of note, the level of miR-301a expression correlated inversely with SMAD4 expression in clinical specimens of human lung cancer. Our findings ascertain that miR-301a is an oncogenic miRNA, which targets SMAD4 to establish an essential mechanism for arsenic-induced carcinogenesis, IL-6/STAT3/miR-301a/SMAD4 signaling pathways.

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Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

Cited by 31 publications

References 52 publications

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes

Malignant Transformation of Human Bronchial Epithelial Cells Induced by Arsenic through STAT3/miR-301a/SMAD4 Loop

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Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

Cited by 31 publications

References 52 publications

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67high) thymocytes

Malignant Transformation of Human Bronchial Epithelial Cells Induced by Arsenic through STAT3/miR-301a/SMAD4 Loop

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Fluoxetine triggers selective apoptosis in inflammation‐induced proliferating (Ki‐67^high) thymocytes