Cadmium ions induce monocytic production of tumor necrosis factor-alpha by inhibiting mitogen activated protein kinase dephosphorylation
Introduction
As a result of the widespread dispersion of cadmium in the environment, humans are constantly exposed to low levels of this metal in drinking water and foodstuffs. An estimated average exposure level of 30–50 μg/day, together with a projected biological half life of 20–30 years, leads to accumulation of significant amounts of cadmium in the human body, especially in kidney and liver. This can be aggravated by additional sources of cadmium, such as cigarette smoke and occupational exposure (Satarug et al., 2003). Cadmium ions (Cd2+) are cytotoxic and inhibit DNA, RNA, and protein synthesis (Beyersmann and Hechtenberg, 1997). Furthermore, even though it is only weakly mitogenic by itself, Cd2+ can interact with cellular signal transduction, induce oxidative stress, and inhibit DNA repair. Cadmium has been classified as carcinogenic in humans, particularly affecting lung and kidney (Beyersmann and Hartwig, 2008).
The effects of Cd2+ are not limited to direct cytotoxicity. Cd2+ can also act at sub-toxic concentrations, which are far more likely to occur in vivo resulting from normal (Satarug et al., 2003) or occupational exposure (Karakaya et al., 1994, Yucesoy et al., 1997). Whereas the most widely investigated effect of sub-toxic exposure to cadmium is its carcinogenicity, this metal also modulates the immune response. Data about the immunotoxicity of cadmium are contradictory; in some cases it stimulates the immune response and reduces susceptibility to pathogens, in others Cd2+ acts as an immunosuppressant, while yet other studies find no effect, even if seemingly identical aspects of immunity were investigated (Koller, 1980, Haase and Rink, 2009b).
It has been shown that treatment of rodents with Cd2+ can induce inflammation (Kataranovski et al., 1998, Dan et al., 2000). Rats injected intraperitoneally with Cd2+ show a rise in activity of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 (Kataranovski et al., 1998, Kataranovski et al., 1999), and a role for TNF-α has been shown in hepatotoxicity resulting from subcutaneous and intravenous administration of cadmium (Kayama et al., 1995b). Furthermore, culture of human peripheral blood mononuclear cells (PBMC) in the presence of Cd2+ led to gene expression of IL-1α, TNF-α, interferon (IFN)-γ, and IL-6, detected by RT-PCR (Marth et al., 2000).
Another group IIb metal, zinc (Zn2+), induces the production of pro-inflammatory cytokines by human PBMC (Wellinghausen et al., 1996). Here, monocytes were identified as the cell type that releases these cytokines (Driessen et al., 1994). A physiological function of Zn2+ was shown upon stimulation of monocytes with lipopolysaccharide (LPS). Here, an increase of intracellular free Zn2+ was observed. This zinc signal inhibited mitogen activated protein kinase (MAPK) phosphatases (MKP), an event that is required for LPS-induced TNF-α secretion (Haase et al., 2008). Cd2+ may have a similar impact on MKPs, because it has been shown to activate MAPKs in monocytic cells (Galan et al., 2000, Misra et al., 2002, Kim et al., 2005).
Aim of this study was to investigate the effect of Cd2+ on TNF-α production by monocytes and the role of MAPKs in these events. We found that sub-toxic doses of cadmium inhibit p38 and ERK 1/2 dephosphorylation, leading to increased MAPK phosphorylation and MAPK-dependent induction of TNF-α in human and murine monocytes/macrophages.
Section snippets
Materials
RPMI 1640 cell culture medium, penicillin, streptomycin, l-glutamine, and phosphate buffered saline (PBS, 1× and 10×) were purchased from Lonza (Verviers, Belgium). Low endotoxin fetal calf serum (FCS) was obtained from PAA (Cölbe, Germany) and was heat inactivated for 30 min at 56 °C prior to use. CdSO4·8/3 H2O (#20920, puriss p.a., ≥99.0% purity with defined limits for trace amounts of other cations) and para-nitrophenyl phosphate were from FLUKA (Schnelldorf, Germany), Zinquin ethyl ester from
Uptake, impact on ROS production, and toxicity of Cd2+ in Raw 264.7 macrophages
The uptake of Cd2+ into the murine macrophage cell line Raw 264.7 was measured with the metal-binding fluorescent probe Zinquin (Fig. 1A). This dye is mainly used to measure free cellular zinc, but also detects Cd2+ by a 5-fold increase in fluorescence upon binding of the metal ion (Zalewski et al., 1993). The uptake of Cd2+ was concentration dependent and slowed down markedly 10 min after its addition.
Several effects of Cd2+ are mediated by reactive oxygen species (ROS). Hence, the production
Discussion
Chronic and acute cadmium intoxication of rodents can induce inflammation (Kataranovski et al., 1998, Dan et al., 2000). Rats injected intraperitoneally with cadmium show a rise in cytoplasmic TNF and IL-6 activity (Kataranovski et al., 1998, Kataranovski et al., 1999), and a role for the pro-inflammatory cytokine TNF-α has been shown in cadmium-mediated hepatotoxicity (Kayama et al., 1995b), whereas IL-6 is induced by cadmium during kidney damage (Kayama et al., 1995a). The mechanism by which
Conflict of interest statement
The authors declare that there are no conflicts of interest.
References (49)
- et al.
Cadmium, gene regulation, and cellular signalling in mammalian cells
Toxicol. Appl. Pharmacol.
(1997) - et al.
Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5
Free Radic. Biol. Med.
(2008) - et al.
Activation of parallel mitogen-activated protein kinase cascades and induction of c-fos by cadmium
Toxicol. Appl. Pharmacol.
(2000) - et al.
Stress-activated protein kinase-dependent induction of c-fos by Cd(2+) is mediated by MKK7
Biochem. Biophys. Res. Commun.
(2000) - et al.
Stimulation of p38 mitogen-activated protein kinase is an early regulatory event for the cadmium-induced apoptosis in human promonocytic cells
J. Biol. Chem.
(2000) The ZIP family of metal transporters
Biochim. Biophys. Acta
(2000)- et al.
In vitro and in vivo effect of mercury, lead and cadmium on the generation of chemiluminescence by human whole blood
Biochem. Pharmacol.
(1989) - et al.
Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling
Exp. Cell Res.
(2003) - et al.
Fluctuations of cellular, available zinc modulate insulin signaling via inhibition of protein tyrosine phosphatases
J. Trace Elem. Med. Biol.
(2005) - et al.
Differential activation of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinases confers cadmium-induced HSP70 expression in 9L rat brain tumor cells
J. Biol. Chem.
(1998)
Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases
Cell
Cadmium-induced renal damage and proinflammatory cytokines: possible role of IL-6 in tubular epithelial cell regeneration
Toxicol. Appl. Pharmacol.
Role of tumor necrosis factor-alpha in cadmium-induced hepatotoxicity
Toxicol. Appl. Pharmacol.
Immunotoxicology of heavy metals
Int. J. Immunopharmacol.
Toxicity and distribution of cadmium administered to rats at sublethal doses
Toxicol. Appl. Pharmacol.
Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1)
Arch. Biochem. Biophys.
Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons
J. Biol. Chem.
Cd2+ versus Zn2+ uptake by the ZIP8 HCO3-dependent symporter: kinetics, electrogenicity and trafficking
Biochem. Biophys. Res. Commun.
Cadmium toxicity in animal cells by interference with essential metals
Biochimie
Low dose cadmium poisoning results in sustained ERK phosphorylation and caspase activation
Biochem. Biophys. Res. Commun.
Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms
Cell Signal.
A global perspective on cadmium pollution and toxicity in non-occupationally exposed population
Toxicol. Lett.
Cadmium evokes inositol polyphosphate formation and calcium mobilization. Evidence for a cell surface receptor that cadmium stimulates and zinc antagonizes
J. Biol. Chem.
Cadmium and cellular signaling cascades: to be or not to be?
Toxicol. Appl. Pharmacol.
Cited by (32)
The adverse impact of cadmium on immune function and lung host defense
2021, Seminars in Cell and Developmental BiologyCadmium induced inflammation and apoptosis of porcine epididymis via activating RAF1/MEK/ERK and NF-κB pathways
2021, Toxicology and Applied PharmacologyCitation Excerpt :One study showed that TPEN induced apoptosis of happocampal neurons by inhibiting Raf/MEK/ERK pathway (Pang et al., 2012). It had been confirmed that RAF1/MEK/ERK signal pathway could trigger apoptosis via the inflammatory factor TNF-α mediated death receptor pathway (Haase et al., 2010). A variety of cytokines and growth factors activated ERK receptor through Ras/Raf/MEK signaling pathway, and ERK participates in apoptosis and inflammation by activating NF-κB (Zhang et al., 2018).
Immunotoxicology of cadmium: Cells of the immune system as targets and effectors of cadmium toxicity
2021, Food and Chemical ToxicologyCitation Excerpt :Activation of redox-sensitive transcription factors NF-κB and AP-1 by Cd, resulted in the expression of genes coding for pro-inflammatory cytokines (Freitas and Fernandes, 2011; Theron et al., 2012). Stimulation of protein kinases ERK1/2 and p38 MAP phosphorylation (via inhibition of phosphatases) led to an increase in Cd-induced production of TNF-α by murine monocyte/macrophage cell line RAW 264.7 (Haase et al., 2010). Activation of ERK1/2 by Cd resulted in vitamin D3 induced maturation of human myelomonocytic cells HL-60 to functional monocytes expressing augmented capacity of phagocytosis and oxidative burst (Ober-Blobaum et al., 2010).
Cadmium induces inflammatory cytokines through activating Akt signaling in mouse placenta and human trophoblast cells
2018, PlacentaCitation Excerpt :An in vivo study showed that oral CdCl2 exposure elevated the level of macrophage inflammatory protein (MIP)-2 mRNA in mouse proximal intestine [19]. An in vitro study found that culture with CdCl2 up-regulated tumor necrosis factor (TNF)-α in primary human monocytes [20]. Moreover, CdCl2 elevated the level of interleukin (IL)-8 in human airway epithelial cells [21].
Cadmium-induced oxidative damages in the human BJAB cells correlate with changes in intracellular trace elements levels and zinc transporters expression
2016, Toxicology in VitroCitation Excerpt :Cd was shown to provoke a number of responses in the cells that involve not only death signaling but also protective reactions against the toxicity (Luparello et al., 2010; Nemmiche et al., 2012). It acts as an immunomodulator at sub-toxic concentrations (Haase et al., 2010) and many of its effects are mediated by oxidative mechanisms. The mechanisms involved in the transport and handling of Cd in target cells are not well defined.
Cadmium induces matrix metalloproteinase-9 expression via ROS-dependent EGFR, NF-κB, and AP-1 pathways in human endothelial cells
2015, ToxicologyCitation Excerpt :Cd and its compounds were classified as human carcinogens based on the evidence from both humans and experimental animals (IARC, 1993). Much effort has been directed to define the role of Cd in tumor metastasis promoted by the following observations: (i) Cd has been widely used in industry and is widely distributed in the earth's crust, air, and water; (ii) the major sources of Cd uptake by humans are food, cigarette smoke, and polyvinylchloride (PVC)- and Cd-related industries (Jarup et al., 1998); (iii) Cd has a high accumulation and long half-life in the human body (Hartwig 2010); (iv) Cd interferes with the cellular antioxidant system and induces the generation of reactive oxygen species (ROS) and inhibits DNA damage repair and DNA methylation (Waisberg et al., 2003); and (v) Cd induces various genes related to tumor metastasis, including HIF-1, VEGF, IL-8, COX-2, TNF-α, and uPAR, which are important for tumor development (Haase et al., 2010; Hyun et al., 2007; Jing et al., 2012; Khoi et al., 2014). In the current study, we found that Cd could induce MMP-9 expression and stimulate cell invasiveness in endothelial cells.