Regulatory effects of zinc on cadmium-induced cytotoxicity in chronic inflammation

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.

Bioactive phytochemicals from Salvia officinalis attenuate cadmium-induced oxidative damage and genotoxicity in rats

“…The elevation of serum cytokine levels in rats treated with Cd in our study is in agreement with previous reports (Bonaventura et al 2017;Markiewicz-Górka et al 2019). These results suggested that exposure to Cd stimulates the cytokines production leading to cellular immune response disorders and all of these disturbances are consequences of the oxidative damage of Cd (Bonaventura et al 2017;Turley et al 2019). These results also con rmed that Cd affects the macrophages M1-type which is accountable for the in ammatory response via the releasing of the pro-in ammatory cytokines (Saqib et al 2018).…”

Cadmium Toxicity: Oxidative Stress, Inflammation and Tissue Injury

“…Results show a reduction of IL-6 production by synergistic action between IL-17 and TNF-α with no induction of local inflammation and limited deposition of Cd in the liver suggesting a safe risk/benefit ratio without inducing toxic effects on other organs [77]. Further to this study, it was demonstrated that the anti-inflammatory effect of Cd on the synoviocytes was reversed by the presence of zinc that competes with Cd for the non-selective transporter, ZIP-8 [78]. An early human study suggested that Cd may hold anti-inflammatory properties such that the metal suppresses inflammation by downregulating pro-inflammatory genes and thereby inhibiting infiltration into the vessel wall [79] [80].…”

Decrease in matrix metalloproteinase‑3 activity in systemic sclerosis fibroblasts causes α2‑antiplasmin and extracellular matrix deposition, and contributes to fibrosis development

“…α2AP expression increased while MMP-3/TIMP-1 ratio decreased in SSc dermal fibroblasts. Bonaventura et al (24) reported that the ratio of MMP-3/TIMP-1 indicates the activity of MMP-3. Hence, we next assessed α2aP expression and MMP-3/TIMP-1 ratio in normal human and SSc dermal fibroblasts by western blotting (normal fibroblasts: n=4, SSc fibroblasts: n=7).…”