Cadmium attenuates the macrophage response to LPS through inhibition of the NF-κB pathway

Cox, Jessica Napolitano; Rahman, Matiur; Bao, Shengying; Liu, Mingjie; Wheeler, Sarah E.; Knoell, Daren L.

doi:10.1152/ajplung.00022.2016

Cited by 39 publications

(22 citation statements)

References 48 publications

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“…Moreover, the impaired immune function of macrophages observed in the referred study was attributed to the inhibition of the transcription factor complex nuclear factor (NF)-κB. Indeed, the NF-κB pathway is a well-known critical activator of genes involved in inflammation and immune function [58]. The exposure to cadmium results in elevated protein concentrations of several pro-inflammatory cytokines and their receptors such as chemokine (C-X-C motif) ligand (CXCL)2, CXCL3, IL-8/CXCL8 and chemokine (C-C motif) ligand-26, IL-6 and IL-1 receptor ligand-1 in human fibroblasts in vitro [59].…”

Section: Alveolar Macrophagesmentioning

confidence: 81%

Cadmium in tobacco smokers: a neglected link to lung disease?

et al. 2018

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Cadmium in tobacco smoke may contribute to the development of pulmonary emphysema. However, there is poor understanding of the mechanisms behind the pathogenic role of cadmium in this and other smoking-related lung diseases. The traditional focus on the total body burden of cadmium, estimated through analysis of urine, may not fully reflect the local burden of cadmium, since it is inhaled by smokers. Thus, assessing the local accumulation of cadmium in the lungs appears more relevant, given that there is tissue-specific retention of cadmium.In this review, we outline the principal sources of cadmium exposure and the clinical effects of occupational exposure. In addition, we review evidence on local cadmium and its association with alterations in innate immunity in tobacco smokers. Moreover, we scrutinise the data on cadmium as a cause of lung disease in translational models.We conclude that cadmium may contribute to smoking-related lung diseases, possibly via an altered redox balance and by making macrophages dysfunctional. However, there is a need for new studies on local cadmium levels and their relation to pathology in long-term tobacco smokers, as well as for more indepth studies on cellular and molecular mechanisms, to elucidate the importance of cadmium in smokingrelated lung diseases.

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Section: Alveolar Macrophagesmentioning

confidence: 81%

Cadmium in tobacco smokers: a neglected link to lung disease?

et al. 2018

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“…Iron and zinc inhibit the ZIP8-mediated uptake of one another [40, 42, 43]. Therefore, these cations have the potential to modulate the impact of zinc on macrophage immune function through competitive uptake and cell signaling [44, 45]. Although, Zinpyr-1 is highly specific for labile zinc it may be limited in its ability to distinguish between particular divalent cations under certain circumstances [46].…”

Section: Resultsmentioning

confidence: 99%

Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition

et al. 2017

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Two vital functions of the innate immune system are to initiate inflammation and redistribute micronutrients in favor of the host. Zinc is an essential micronutrient used in host defense. The zinc importer ZIP8 is uniquely induced through stimulation of the NF-κB pathway by LPS in monocytes and functions to regulate inflammation in a zinc-dependent manner. Herein we determined the impact of zinc metabolism following LPS-induced inflammation in human macrophages. We observed that ZIP8 is constitutively expressed in resting macrophages and strikingly elevated following LPS exposure, a response that is unique compared to the 13 other known zinc import proteins. During LPS exposure, extracellular zinc concentrations within the physiological range markedly reduced IL-10 mRNA expression and protein release but increased mRNA expression of TNFα, IL-8, and IL-6. ZIP8 knockdown inhibited LPS-driven cellular accumulation of zinc and prevented zinc-dependent reduction of IL-10 release. Further, zinc supplementation reduced nuclear localization and activity of C/EBPβ, a transcription factor known to drive IL-10 expression. These studies demonstrate for the first time that zinc regulates LPS-mediated immune activation of human macrophages in a ZIP8-dependent manner, reducing IL-10. Based on these findings we predict that macrophage zinc metabolism is important in host defense against pathogens.

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“…Incubation with Cd at 30–100 μ M markedly decreased cell viability at 24 h. Thus, we performed all experiments with the concentration of 10 and 30 μ M of Cd, which has been employed in many studies to examine early genetic alteration and inflammatory responses. 10 , 12 , 13 , 14 , 15 …”

Section: Methodsmentioning

confidence: 99%

Cadmium-induced ER stress and inflammation are mediated through C/EBP–DDIT3 signaling in human bronchial epithelial cells

et al. 2017

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Cadmium (Cd), a major component of cigarette smoke, disrupts the normal functions of airway cells and can lead to the development of various pulmonary diseases such as chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms involved in Cd-induced pulmonary diseases are poorly understood. Here, we identified a cluster of genes that are altered in response to Cd exposure in human bronchial epithelial cells (BEAS-2B) and demonstrated that Cd-induced ER stress and inflammation are mediated via CCAAT-enhancer-binding proteins (C/EBP)-DNA-damaged-inducible transcript 3 (DDIT3) signaling in BEAS-2B cells. Cd treatment led to marked upregulation and downregulation of genes associated with the cell cycle, apoptosis, oxidative stress and inflammation as well as various signal transduction pathways. Gene set enrichment analysis revealed that Cd treatment stimulated the C/EBP signaling pathway and induced transcriptional activation of its downstream target genes, including DDIT3. Suppression of DDIT3 expression using specific small interfering RNA effectively alleviated Cd-induced ER stress and inflammatory responses in both BEAS-2B and normal primary normal human bronchial epithelial cells. Taken together, these data suggest that C/EBP signaling may have a pivotal role in the early induction of ER stress and inflammatory responses by Cd exposure and could be a molecular target for Cd-induced pulmonary disease.

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Cadmium attenuates the macrophage response to LPS through inhibition of the NF-κB pathway

Cited by 39 publications

References 48 publications

Cadmium in tobacco smokers: a neglected link to lung disease?

Cadmium in tobacco smokers: a neglected link to lung disease?

Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition

Cadmium-induced ER stress and inflammation are mediated through C/EBP–DDIT3 signaling in human bronchial epithelial cells

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