Abstract
ObjectivesZinc (Zn) has major effects on immune system activation while Cadmium (Cd) has anti-inflammatory and anti-proliferative effects in several chronic inflammatory contexts. The aim of this work was to investigate by which mechanisms Zn could compete with Cd and eventually counteract its deleterious effects. Rheumatoid arthritis (RA) synoviocytes exposed to cytokines were used as a model of chronic inflammation; osteoarthritis (OA) synoviocytes were used as control.MethodsCell/medium fractionation constants were analyzed for different metals by inductively-coupled-plasma mass-spectrometry by comparison to the 70Zn spike. Interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were used to mimic inflammation. Gene expression of ZIP-8 importer, metallothioneins-1 (MT-1s) and the ratio between metalloprotease-3 and the tissue inhibitor of metalloproteinases (MMP-3)/TIMP-1) were evaluated after pre-exposure to cytokines and Cd, with or without the addition of exogenous Zn (0.9 ppm). Cell viability was measured by neutral red assay and IL-6 production by ELISA.ResultsSynoviocytes selectively absorbed and retained Cd in comparison to Zn. Metal import increased with IL-17/TNF-α exposure, through the enhanced ZIP-8 expression. Zn did not modify ZIP-8 expression, while Cd reduced it (p<0.05). Zn induced a reduction of Cd-induced MT-1s expression, in particular of MT-1X (3-fold), and subsequently the final intra-cellular content of Cd. By reducing Cd accumulation in cells, Zn reversed Cd anti-proliferative and anti-inflammatory effects but preserved the low MMP-3/TIMP-1 ratio induced by Cd, which was enhanced by inflammatory conditions.ConclusionZinc counteracts the deleterious effect of Cd by reducing its import and accumulation in the cell, without the reactivation of destructive pathways such as MMPs.
Highlights
Zinc (Zn) and cadmium (Cd) belong to the group 12 of divalent metals and have similar characteristics, like chemical properties, homeostasis regulation and oxidative stress induction mechanisms [1,2]
Zn induced a reduction of Cdinduced MT-1s expression, in particular of MT-1X (3-fold), and subsequently the final intracellular content of Cd
By reducing Cd accumulation in cells, Zn reversed Cd anti-proliferative and anti-inflammatory effects but preserved the low matrix degradation through the metalloproteases (MMPs)-3/TIMP-1 ratio induced by Cd, which was enhanced by inflammatory conditions
Summary
Zinc (Zn) and cadmium (Cd) belong to the group 12 of divalent metals and have similar characteristics, like chemical properties, homeostasis regulation and oxidative stress induction mechanisms [1,2]. Cd replaces Zn in Zn-MT bonds without changing their shape and the cellular detoxification action against Cd takes place through MTs. The binding of Cd to MTs is a detoxification mechanism, saturating at high concentrations of Cd. Even if the affinity of Cd for MTs is the strongest, in some models a large supply of Zn has a protective role against the deleterious effects of Cd-exposure [7] through the replacement of Cd by Zn [8]. In contrast Cd inhibits the activity of anti-oxidative enzymes and the mitochondrial electron transport-chain [11], interferes with metalloproteins [12], inhibits the humoral and cellular immune response at low doses [13,14] and eventually enhances apoptosis or cell proliferation [15,16]
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