Role Of Metallothionein Research Articles

Metallothioneins in Inflammatory Bowel Diseases: Importance in Pathogenesis and Potential Therapy Target.

Immunological disorders, increased oxidative stress, and damage to the epithelial barrier play an important role in the pathogenesis of inflammatory bowel diseases (IBDs). In the treatment of patients with Crohn's disease (CD) and ulcerative colitis (UC), it is increasingly common to use biological drugs that selectively affect individual components of the inflammatory cascade. However, administering the medicines currently available does not always result in obtaining and maintaining remission, and it may also lead to the development of resistance to a given agent over time. Metallothioneins (MTs) belong to the group of low molecular weight proteins, which, among others, regulate the inflammation and homeostasis of heavy metals as well as participating in the regulation of the intensity of oxidative stress. The results of the studies conducted so far do not clearly indicate the role of MTs in the process of inflammation in patients with IBD. However, there are reports that suggest the possibility of using MTs as a potential target in the treatment of this group of patients.

Plant Metallothioneins as Regulators of Environmental Stress Responses

Scientific research has focused to delineate the core aspects of stress tolerance mechanisms and to apply the crucial components for enhancing the tolerance of plants and their growth under stressed environments. Metallothioneins (MTs) are known to play pivotal roles in stress regulation. They are known in bacteria, fungi, and all other eukaryotic organisms. MTs are low molecular weight, cysteinerich proteins. They are important metal chelators and also possess antioxidant properties. MTs work upon reactive oxygen species (ROS), whose production is induced by different stresses and is known to damage various cellular biomolecules. MT proteins are classified into two classes, plant MTs belong to class II type, while animal MTs belong to class I type. MTs have been investigated in the vast number of plant species and their crucial roles in stress modulation has been uncovered. Hence, MTs are a promising tool for stress management, acting as essential stress biomarkers and ensuring food security in the coming future to achieve sustainable development goals worldwide. This review discusses the roles of MTs in plants under different abiotic stresses, including drought, salinity, low temperature, light, in oxidative stress regulation and heavy metals homeostasis and detoxification including toxic nanoparticle management in plants.

The role of metallothioneins in the formation of hierarchical mechanisms of resistance to toxic compounds in young and old animals on the example of copper sulfate

We used classical methods of biochemistry, chromolithography, atomic adsorption spectrometry for the determination of copper ions and MALDI-TOF mass spectrometry for the determination of metallothioneins. We have found sequential administration of small doses of copper sulfate provided the formation of resistance to subsequent lethal doses of copper sulfate. Age-dependent differences in the adaptive response match with the difference in the metallothioneins content in liver cells. In this case of adaptation formation, there was not only an increase in metallothioneins, but also a change in the intracellular distribution of copper ions. We revealed that a multiple increase in copper ions in mitochondria and endoplasmic reticulum of liver cells was accompanied by a slight decrease in the activity of antioxidant enzymes included in their composition. It has been suggested that metallothioneins are involved not only in the accumulation and retention of copper ions, but also in active inter-protein swap. Age-dependent differences in resistance, adaptability and long-term effects of copper ions are due to differences in the metabolic systems of copper metabolism before the toxic doses administration of copper sulfate, i.e. difference in initial states.

Metallothionein levels in gingival crevicular fluid, saliva, and serum of smokers and non-smokers with chronic periodontitis.

Metallothionein (MT), a cysteine rich protein is involved as a radical scavenger in several pathological conditions associated with oxidative stress; however, its role in periodontal disease still remains elusive. The aim of this cross-sectional study is to determine the serum, saliva and gingival crevicular fluid (GCF) levels of MT in smokers (S) and non-smokers (NS) with chronic periodontitis (CP), and compare them with those of periodontally healthy (PH) individuals. A total of 85 participants were enrolled: 45 patients with CP (23 S [CP+S] and 22 NS [CP+NS]) and 40 PH individuals (20 S [PH+S] and 20 NS [PH+NS]). In all the study participants, clinical periodontal parameters (plaque index, gingival index, sulcus bleeding index, probing depth, and clinical attachment level) were recorded and samples of serum, saliva and GCF were collected. Enzyme-linked immunosorbent assay was used to determine the levels of MT in the samples. All periodontal clinical parameters were significantly higher in the CP groups as compared to PH groups (P<0.05). MT levels in CP+S group were significantly raised in comparison to other three groups. There was no statistically significant difference in MT levels among CP+NS and PH+S groups (P>0.05); however, relatively higher levels were observed in GCF and saliva in CP+NS group. When all the study groups were observed together, MT levels were positively correlated with clinical parameters. Results of present study suggest that smoking and CP can induce the synthesis of MT owing to increased oxidative stress and heavy metals intoxication. Further longitudinal studies with large sample size and an interventional arm are needed to substantiate the role of MT as a potential biomarker in periodontitis.

Metallothionein 1 Overexpression Does Not Protect Against Mitochondrial Disease Pathology in Ndufs4 Knockout Mice.

Mitochondrial diseases (MD), such as Leigh syndrome (LS), present with severe neurological and muscular phenotypes in patients, but have no known cure and limited treatment options. Based on their neuroprotective effects against other neurodegenerative diseases in vivo and their positive impact as an antioxidant against complex I deficiency in vitro, we investigated the potential protective effect of metallothioneins (MTs) in an Ndufs4 knockout mouse model (with a very similar phenotype to LS) crossed with an Mt1 overexpressing mouse model (TgMt1). Despite subtle reductions in the expression of neuroinflammatory markers GFAP and IBA1 in the vestibular nucleus and hippocampus, we found no improvement in survival, growth, locomotor activity, balance, or motor coordination in the Mt1 overexpressing Ndufs4-/- mice. Furthermore, at a cellular level, no differences were detected in the metabolomics profile or gene expression of selected one-carbon metabolism and oxidative stress genes, performed in the brain and quadriceps, nor in the ROS levels of macrophages derived from these mice. Considering these outcomes, we conclude that MT1, in general, does not protect against the impaired motor activity or improve survival in these complex I-deficient mice. The unexpected absence of increased oxidative stress and metabolic redox imbalance in this MD model may explain these observations. However, tissue-specific observations such as the mildly reduced inflammation in the hippocampus and vestibular nucleus, as well as differential MT1 expression in these tissues, may yet reveal a tissue- or cell-specific role for MTs in these mice.

High-dose dietary supplementation with zinc prevents gut inflammation: Investigation of the role of metallothioneins and beyond by transcriptomic and metagenomic studies.

Although it is known that zinc has several beneficial roles in the context of gut inflammation, the underlying mechanisms have not been extensively characterized. Zinc (Zn) is known to be the primary physiological inducer of the expression of the metallothionein (MT) superfamily of small stress-responsive proteins. The expression of MTs in various tissues is induced or enhanced (including the gastrointestinal tract (GIT)) by a variety of stimuli, including infection and inflammation. However, the MTs' exact role in inflammation is still subject to debate. In order to establish whether or not MTs are the sole vectors in the Zn-based modulation of intestinal inflammation, we used transcriptomic and metagenomic approaches to assess the potential effect of dietary Zn, the mechanisms underlying the MTs' beneficial effects, and the induction of previously unidentified mediators. We found that the expression of endogenous MTs in the mouse GIT was stimulated by an optimized dietary supplementation with Zn. The protective effects of dietary supplementation with Zn were then evaluated in mouse models of chemically induced colitis. The potential contribution of MTs and other pathways was explored via transcriptomic analyses of the ileum and colon in Zn-treated mice. The microbiota's role was also assessed via fecal 16S rRNA sequencing. We found that high-dose dietary supplementation with Zn induced the expression of MT-encoding genes in the colon of healthy mice. We next demonstrated that the Zn diet significantly protected mice in the two models of induced colitis. When comparing Zn-treated and control mice, various genes were found to be differentially expressed in the colon and the ileum. Finally, we found that Zn supplementation did not modify the overall structure of the fecal microbiota, with the exception of (i) a significant increase in endogenous Clostridiaceae, and (ii) some subtle but specific changes at the family and genus levels. Our results emphasize the beneficial effects of excess dietary Zn on the prevention of colitis and inflammatory events in mouse models. The main underlying mechanisms were driven by the multifaceted roles of MTs and the other potential molecular mediators highlighted by our transcriptomic analyses although we cannot rule out contributions by other factors from the host and/or the microbiota.

Uptake and detoxification of trace metals in estuarine crabs: insights into the role of metallothioneins.

The detoxification process of trace metals in the estuarine burrowing crab Neohelice granulata, after previously being exposed to anthropogenic pressures in the field, is described for the first time. The objectives of this study were (a) to assess the metal content (Cd, Cu, Pb, Zn, Mn, Ni, Cr, Fe) in the sediments and the uptake of these elements in the hepatopancreas of N. granulata; (b) to quantify trace metal concentrations in the hepatopancreas before and after the detoxification experiment; and (c) to relate this information to metallothionein (MT) induction or reversibility. The detoxification assay was performed for 25days with artificial seawater under controlled conditions in a culture chamber. The results showed higher uptake and bioaccumulation of Zn and Cu from the sediments, and the hepatopancreas exhibited increased levels of Zn and lower concentrations of the rest of the metals and MTs after the assay, mainly Fe and Mn that were significantly lower. We conclude that trace metals could be translocated to and accumulated in the hepatopancreas, the main metabolic organ, and then eliminated under controlled conditions with corresponding reversibility of MTs. Graphical abstract.

Metallothionein Cd4S11 cluster formation dominates in the protection of carbonic anhydrase.

Metallothioneins (MTs) are ubiquitous proteins vital for essential metal homeostasis and heavy metal detoxification. The twenty-cysteinyl mammalian metallothioneins protect the proteome by sequestering heavy metals into thermodynamically stable metal thiolate structures when metalated with seven Cd2+. At physiological pH, the first metal (M) thiolate (SCys) structures formed involve M(SCys)4 terminal thiolates. With higher metal loading, M4(SCys)11 and M3(SCys)9 clusters form. As a regulator of the metallome, it is necessary to understand metal sequestration properties of MT in solution with other metalloproteins. We report that the association between apo-MT and apo-carbonic anhydrase (CA) enhances the formation of the protective mode of MT, in which Cd4(SCys)11-clusters form at much lower concentration levels than for the free apo-MT at physiological pH. Using stopped-flow kinetics and electrospray ionization mass spectrometry, we quantified this protective effect, determining that it is significant at pH 7.4, but the effect diminishes at pH 5.0. We report for the first time, the absolute stepwise binding constants of Cd2+ binding to human MT1a both in the presence and absence of CA through calibration by the known binding constant of Cd2+ to bovine CA. We report that this protein association affects the Cd2+ metalation rates of MT. The data support the physiological role of MTs as protectors of the metalloproteome from the toxic effects of Cd2+.

Metallothionein Expression and its Influence on the In Vitro Biological Behavior of Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is the most common tumor in the salivary glands, often presenting with recurrence and metastasis due to its high invasive capacity. Metallothionein (MT), a zinc storage protein that supplies this element for protease activity, is probably related to mucoepidermoid carcinoma behavior. This prompted us to characterize a cell line derived from mucoepidermoid carcinoma and to correlate metallothionein expression with transforming growth factor-α (TGF-α), tumor necrosis factor-α (TNF-α) and matrix metalloproteinases (MMPs). Transcriptomic analysis and cytogenetic assays were performed to detect the expression of genes of interest and cellular chromosomal alterations, respectively. MEC cells with a depleted metallothionein 2A (MT2A) gene were subjected to Western blot to correlate metallothionein expression with growth factors and MMPs. Additionally, cells with depleted MT were subjected to migration and invasion assays. The transcriptomic study revealed reads mapped to cytokeratins 19 and AE1/AE3, α-smooth muscle actin, vimentin, and fibronectin. Cytogenetic evaluation demonstrated structural and numerical alterations, including the translocation t(11;19)(q21;p13), characteristic of MEC. Metallothionein depletion was correlated with the decreased expression of TGF-α and MMP-9, while TNF-α protein levels were augmented. Migration and invasion activity were diminished after metallothionein silencing. Our findings suggest an important role of MT in MEC invasion, through the regulation of proteins involved in this process.

Expression of metallothionein in oral squamous cell carcinoma: A systematic review.

Free radicals are chemical particles containing one or more unpaired electrons, which may be part of the molecule making them highly reactive species. The free radicals are also known to play a dual role in biological systems, as they can be either beneficial or harmful. It has been proven that there are numerous mechanisms participating in the protection of a cell against free radicals. In this systematic review, we have reviewed metallothioneins (MTs) which are a small, cysteinerich and heavy metalbinding protein, that participates in an array of protective stress responses. The aim of this study was to systematically evaluate the role of MT in oral squamous cell carcinoma (OSCC). In this systematic review, we have found that in 9 studies involving 1340 cases and 542 controls concluded that MT was found to be present in the cytoplasm as well as the nucleus of the tumor tissue in 66.6% of the articles using immunohistochemistry and 11.1% of the articles reported the mosaic pattern of expression of MT in OSCC.

Role of Metallothionein in Transcriptional Regulation by Metal-Responsive Element-Binding Transcription Factor 1

Role of Metallothionein in Transcriptional Regulation by Metal-Responsive Element-Binding Transcription Factor 1

The adaptive immune role of metallothioneins in the pathogenesis of diabetic cardiomyopathy: good or bad.

Diabetes is a metabolic disorder characterized by hyperglycemia, resulting in low-grade systemic inflammation. Diabetic cardiomyopathy (DCM) is a common complication among diabetic patients, and the mechanism underlying its induction of cardiac remodeling and dysfunction remains unclear. Numerous experimental and clinical studies have suggested that adaptive immunity, especially T lymphocyte-mediated immunity, plays a potentially important role in the pathogenesis of diabetes and DCM. Metallothioneins (MTs), cysteine-rich, metal-binding proteins, have antioxidant properties. Some potential mechanisms underlying the cardioprotective effects of MTs include the role of MTs in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant activity. Moreover, metal homeostasis, especially MT-regulated zinc homeostasis, is essential for immune function. This review discusses aberrant immune regulation in diabetic heart disease with respect to endothelial insulin resistance and the effects of hyperglycemia and hyperlipidemia on tissues and the different effects of intracellular and extracellular MTs on adaptive immunity. This review shows that intracellular MTs are involved in naïve T-cell activation and reduce regulatory T-cell (Treg) polarization, whereas extracellular MTs promote proliferation and survival in naïve T cells and Treg polarization but inhibit their activation, thus revealing potential therapeutic strategies targeting the regulation of immune cell function by MTs.

Regulatory role of metallothionein-1/2 on development of sex differences in a high-fat diet-induced obesity

AimsTo evaluate the role of metallothionein (MT) in sex differences of obesity, we examined the effect of MT on regulation of lipid accumulation in female and male wild type (WT) and MT1/MT2-null (MT-KO) mice. Main methodsMale and female WT and MT-KO mice fed standard diet (SD) or high-fat diet (HFD) for 35 weeks. Surgical castration in male mice was also performed to examine the effects of androgen on fat accumulation under HFD condition. Key findingsThe fat mass and size of adipocytes in white adipose tissue (WAT) was greater in adult MT-KO mice than in WT mice after 35 weeks of SD feeding without gender differences, suggesting a role of MT in limiting WAT development during normal growth in both sexes. In female mice fed HFD, weights of WAT and body were greater in MT-KO mice than in WT mice, indicating that MT had a preventive role against excess fat accumulation. In male mice fed HFD, WAT weight hardly increased in MT-KO mice compared to the increase in WT mice. Surgically castrated WT males fed HFD had lower WAT weight compared with sham-treated mice, although castrated MT-KO males fed HFD had greater increases in WAT weight compared with sham-treated mice and castrated WT males. SignificanceThese data suggest that MT could enhance the preventive action of estrogen against excess fat accumulation, on the contrary, MT augmented the ability of androgen to increase fat accumulation. MT may act to modify the susceptibility to obesity under sex hormones.

Seasonal variation of heavy metals and metallothionein contents in Asian swamp eels, Monopterus albus (Zuiew, 1793) from Tumpat, Kelantan, Malaysia

BackgroundLevels of toxic metal exposure in indigenous inhabitants are key bioindicators of the severity of environmental contamination. This study measured the seasonal variation of heavy metals and metallothionein (MT) contents in Asian swamp eels (Monopterus albus) from a paddy field situated in Tumpat, Kelantan, Malaysia, to identify prevalence, patterns and associations and togain insight on the suitability of MT as a biomarker for metal exposure.MethodsGill, muscle and liver tissues of M. albus (n = 50) sampled during the ploughing, seedling, growing and harvesting phases of rice growing were collected. The concentrations of copper (Cu), zinc (Zn), lead (Pb), nickel (Ni), and cadmium (Cd) in these tissues were determined by flame atomic absorption spectrometry. MT from each sample was isolated and purified, and subsequently quantitated using UV spectrophotometry. Associations between metal and MT concentrations, season and tissue type were evaluated using Pearson correlation and ANOVA with post-hoc Tukey HSD analysis.ResultsZn was present in higher quantities in gill and liver tissues, while Cu levels were elevated solely in liver. Patterns of non-essential metal accumulation were varied: Cd was detected in low concentrations in all tissues, while Pb and Ni were abundant in gill tissues across all seasons. MT concentration in liver tissue was consistently higher than that found in muscle or gill tissue, except during the growing phase. Moreover, significant correlations (P < 0.05) were observed for Cd, Ni, and Zn when MT was employed as metal exposure biomarker. However, no significant association was found between high Pb and Ni levels and MT concentration in gill tissue.Variation of bioaccumulation rates of heavy metals among the different tissues was observed. Some of these metal concentration differences were found to be associated with MT concentration and, by extension, to its high metal-binding capacity.ConclusionsSignificant liver MT-Zn, MT-Cd, and MT-Ni correlations found in this study emphasised the role of metallothionein as a biomarker for exposure of zinc, cadmium and nickel metals in M. albus.

Changes in copper, zinc and cadmium distributions in the liver of Formosan squirrels with characteristic high copper accumulation.

We discovered previously that Formosan squirrels (Callosciurus erythraeus) accumulate copper (Cu) in their livers at levels averaging 1700 μg per dry g (approximately 420 μg per wet g). In the current study, we investigated the relationship between Cu accumulation and hepatic injury, and we determined the distribution and chemical form of Cu in the liver supernatant. In particular, we explored the role of metallothionein in the liver supernatant. We observed no significant differences in hepatic Cu concentration between squirrels that showed pathological changes in the liver and those that did not. Serum alanine aminotransferase activity did not increase with increasing hepatic Cu concentration. These results suggest that abnormal Cu accumulation in the livers of Formosan squirrels does not induce severe hepatic injury. We found that 26.7% of the Cu in the liver was distributed to the supernatant, and only 11.0% of the Cu in the liver was bound to metallothionein, suggesting that metallothionein in the hepatic supernatant does not contribute to detoxification of excess Cu in Formosan squirrels.

Role of metallothionein-like cadmium-binding protein (MTLCdBP) in the protective mechanism against cadmium toxicity in the testis.

The role of metallothionein (MT)-like cadmium (Cd) binding protein (MTLCdBP) in protecting the testes against Cd toxicity was examined. In the acute Cd exposure treatment, cadmium chloride was intraperitoneally injected at 2 mg Cd/kg to Wistar male rats. In the chronic Cd toxicity treatments, 20 mg Cd/kg/d was orally administered for 5 d a week for 5, 10, and 15 wk. MT (-I,-II) and MTLCdBP were measured using ELISA and Cd-Hem methods, respectively. Testicular tissues were immunostained with antibodies of MT-I,-II, MT-III, and MTLCdBP. Expression of HO1, OGG, iNOS, COX2, and p53 was measured by RT-PCR. Cd concentration in the testis increased dose-dependently in response to Cd exposure. MTLCdBP concentration increased markedly with increasing Cd accumulation. Significant increases in expression of iNOS, HO1, COX2, and OGG1 were observed in the acute exposure treatment. In the chronic oral administration group, expression of MT-I, MT-II, MT-III, iNOS, HO1, and COX2 did not change. Positive immunostaining of MTLCdBP was observed in testicular interstitial tissue. In the testis protected from Cd toxicity, MTLCdBP induction increased significantly with increasing Cd accumulation. Our results suggest that MTLCdBP plays an important role in protecting the testis against Cd toxicity.

Mass spectrometric imaging of cysteine rich proteins in human skin

Looking insight pathological processes, metallothioneins (MTs) are considered to be potential biomarkers for monitoring of a development of various types of diseases, such as cancer. The early identification of the MTs in biological tissues could be important tool for the estimation of appropriate clinical therapy. Therefore, here we investigated the application of matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) together with immunohistochemical analyses (IHC) using MT-1/2 antibody for MT detection in formalin-fixed paraffin-embedded (FFPE) biopsy specimens of human skin. Principal component analyses revealed differences in the peptide/protein profiles separating healthy skin from the carcinoma specimens. Statistically significant ion peaks at m/z 6038, 6300, 6676, and 7026 were more frequently detected in squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. Using IHC, we found that MT-1/2 was significantly higher in SCC and melanoma compared to healthy skin. Surprisingly, significantly low levels of MT-1/2 were found in BCC. On one side, the results indicate important role of MTs in melanoma occurrence and progression, as on the second side, there are hidden processes associated with MTs based on differences of the occurrence of the MS peaks, which could be associated with cycling of MTs isoforms.

Cloning, characterization and expression analysis of metallothioneins from Ipomoea aquatica and their cultivar-dependent roles in Cd accumulation and detoxification

To explore the possible roles of metallothioneins (MTs) played in cadmium (Cd) accumulation of water spinach, three IaMT genes, IaMT1, IaMT2 and IaMT3 in a high-shoot-Cd (T308) and a low-shoot-Cd accumulation cultivar (QLQ) were cloned, characterized, and quantitated. Gene expression analysis suggested that the expression of the IaMTs was differentially regulated by Cd stress in different cultivars, and T308 showed higher MTs expression overall. Furthermore, only shoot IaMT3 expression was cultivar dependent among the three IaMTs. Antioxidant analysis showed that the high production of IaMTs in T308 should be associated with its high oxidation resistance. The role of IaMTs in protecting against Cd toxicity was demonstrated in vitro via recombinant E. coli strains. The results showed that IaMT1 correlated with neither Cd tolerance nor Cd accumulation of E. coli, while IaMT2 conferred Cd tolerance in E. coli, IaMT2 and IaMT3 increased Cd accumulation in E. coli. These findings help to clarify the roles of IaMTs in Cd accumulation, and increase our understanding of the cultivar-dependent Cd accumulation in water spinach.

Abstract A022: Role of metallothionein in the pathogenesis of prostate cancer

Abstract Metallothionein (MT) is a metal binding protein of low molecular weight. It is involved in metal homeostasis, cell differentiation, proliferation, and detoxification of heavy metals. Neoplastic transformation in prostate cancer is attributed to elevated levels of metallothionein. We studied the expression of MT in prostate tissues. Immunohistochemistry (IHC) of 35 prostate cancer patients was performed to evaluate the expression of MT and then correlated with the expression profiles of epithelial TRAIL (Tumor necrosis factor related apoptosis inducing ligand), stromal TRAIL, decoy receptors (DcR1 and DcR2), death receptors (DR4 and DR5), nuclear factor κB (NF-κB), and FLICE inhibitory protein (FLIP). We also correlated expression patterns of these proteins using Pearson correlation with clinical histopathologic factors and determined their influence on overall survival of patients. Elevated levels of MT were observed in cancer tissues as compared to benign controls. Expression levels of epithelial TRAIL, DcR1, DcR2, DR4, DR5, NF-κB, and FLIP were also enhanced in cancer tissue samples. Age at diagnosis was significantly associated with stage (R= -0.467, p=0.046), MT (R= -0.419, p=0.012), DcR1 (R= 0.355, p=0.036) and sTRAIL (R= 0.553, p= 0.001). NF-κB significantly correlated with DR5 expression (R= 0.408, p = 0.015) in tumor tissues. Better survival was observed in patients with MT negative expression (p=0.467). Elevated levels of MT in prostate cancer patients and its positive correlation with FLIP and DcR1 depict its role as an antiapoptotic moiety. Further exploration of the role of MT in prostate cancer pathogenesis could help in establishing MT as a potential therapeutic target. Citation Format: Sobia Hamid, Mariam Anees. Role of metallothionein in the pathogenesis of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A022.

The role of metallothionein in a dinitrofluorobenzene-induced atopic dermatitis-like murine model

Atopic dermatitis (AD), one of the most common chronic eczematous skin disorders, is associated with cutaneous hyperactivity as a response to environmental triggers. Metallothionein (MT) plays a constitutive defensive role in the response to noxious stimuli. However, the role of MT in AD development is unclear. Using an AD-like murine model created by the topical application of 2.4-dinitrofluorobenzene, we studied the dynamic pattern of MT expression on AD development. AD-like lesions were evaluated based on the development of erythema, edema, exfoliation, scaling, increased thickness, and increased weight of lesional skin. These characteristics of AD-like lesions and thymic stromal lymphopoietin (TSLP) expression peaked at Day 1 of the establishment of our model and gradually alleviated over time. The MT expression in lesional skin was increased and peaked at Day 3. By immunostaining, increased expression of MT was translocated from the cytoplasm to the nucleus. MT-1/2 knockout (MT−/−) mice and wild type (MT+/+) mice were also used to evaluate the role of MT on AD. MT−/− mice had greater edema scores, thickness, lesional skin weight, as well as more CD4+ T cells, TSLP, superoxide dismutase, and NDUFAF1. These results suggest that MT may play a protective role against AD development, and that antioxidant and nuclear protective mechanisms may be involved.