Elsevier

Toxicology Letters

Volume 198, Issue 2, 5 October 2010, Pages 152-158
Toxicology Letters

Cadmium ions induce monocytic production of tumor necrosis factor-alpha by inhibiting mitogen activated protein kinase dephosphorylation

https://doi.org/10.1016/j.toxlet.2010.06.010Get rights and content

Abstract

Cadmium ions (Cd2+) are carcinogenic and have cytotoxic effects in a variety of organisms. In addition to its direct cytotoxicity, Cd2+ acts as an immunomodulator at sub-toxic concentrations. Among other influences Cd2+ can induce inflammation, but the molecular basis for this effect is not well investigated. In this manuscript, we analyze the impact of Cd2+ on monocytes/macrophages, which are potent producers of pro-inflammatory cytokines, finding that Cd2+ treatment induced tumor necrosis factor (TNF)-α secretion. Based on the observation that another group IIb metal, zinc (Zn2+), has a physiological role in these events, we investigated if Cd2+ acts on the same molecular targets. Like Zn2+, Cd2+ inhibits phosphatases, and hereby dephosphorylation of mitogen activated protein kinases (MAPK). Consequently, treatment of cells with Cd2+ resulted in stimulation of ERK 1/2 and p38 MAPK phosphorylation. Furthermore, Cd2+-induced release of TNF-α from primary human monocytes was blocked by inhibitors for ERK 1/2 (U0126) and p38 MAPK (SB202190), demonstrating that MAPKs are involved in the induction of TNF-α by Cd2+.

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.

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