metallothionein and Arthritis--Rheumatoid

Topics: Arthritis, Rheumatoid; Auranofin; Collagenases; Glutathione Peroxidase; Gold Compounds; Humans; Metallothionein; Organometallic Compounds; Serum Albumin; Sulfhydryl Compounds; Thioredoxin-Disulfide Reductase; Tissue Distribution

Evidence concerning a role for metallothionein (MT) in human disease is reviewed. Current knowledge of MT is juxtaposed with our understanding of the pathogenesis of disease. MT is known to modulate three fundamental processes: 1) the release of gaseous mediators such as hydroxyl radical or nitric oxide; 2) apoptosis, and 3) the binding and exchange of heavy metals such as zinc, cadmium or copper. The capability to specifically manipulate MT levels in cells and in mice is beginning to provide answers regarding how MT could impact complex disease scenarios. Associations among MT and several diseases, including cancer, circulatory and septic shock, coronary artery disease, and Alzheimer's disease have been made. Strong evidence exists that MT modulates the immune system. The primary function of MT remains unknown.

Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Cadmium; Copper; Diabetes Mellitus; Free Radicals; HeLa Cells; Humans; Immune System; Metallothionein; Mice; Models, Biological; Neoplasms; Nervous System Diseases; Nitric Oxide; Protein Binding; Shock; Zinc

Insufficient therapeutic effect of auranofin (AF), used in the treatment of rheumatoid arthritis, is found in about 8% of the patients included in clinical trials until now. The mechanisms of resistance to gold-containing drugs are not known, but one reason might be acquired drug resistance. We have studied the relationship between the effects of gold and concentration of the cytoplasmic metal-binding protein metallothionein (MT), in order to evaluate MT as a possible contributing factor to resistance against AF. Different strains of cultured human epithelial cells derived from normal skin, treated with AF, were used as models. The experiments indicate two possible mechanisms for resistance against AF in cells: 1) binding of gold to pre-existent cadmium-induced MT or to de novo AF-induced MT, and 2) the cells' ability to keep the intracellular gold concentration at a low level. AF apparently causes a rapid and pronounced increase of MT-content in these cells. Preliminary results also indicated that AF causes increase of MT-content in human rheumatoid synovial cells, grown as primary cultures. These findings may have two clinical implications: 1) AF-induced MT may decrease therapeutic response, and 2) decrease the toxicity of AF.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Auranofin; Aurothioglucose; Cells, Cultured; Drug Resistance; Gold; Humans; Metallothionein; Protein Binding

Surfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA.. One-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed.. Serum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings.. This study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation.. (j.nr NCT00209859).

Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; Arthrography; Female; Genotype; Health Status; Humans; Male; Metallothionein; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Pulmonary Surfactant-Associated Protein D; Reference Values; Surveys and Questionnaires; Young Adult

Periodontitis (PD) and rheumatoid arthritis (RA) are causally linked by their common inflammatory responses, yet it is largely unknown if these inflammatory responses might have an impact on salivary metallothionein (MT), zinc (Zn), and calcium (Ca) content. In this study, we analysed salivary concentrations of pro-inflammatory (IFN-γ, IL-6, and IL-17) and anti-inflammatory (IL-4 and IL-10) cytokines, as well as MT, Zn, and Ca in four groups of participants, namely control (without PD or RA, n = 21), PD (n = 21), RA (n = 21), or RAPD (n = 19). As expected, an increased amount of salivary pro-inflammatory cytokines were observed in the PD, RA, and RAPD groups. While Ca concentration was not significantly different between the groups, Zn concentration was lower in the PD, RA, and RAPD groups compared to the control group (p < 0.05). These groups also expressed higher MT/Zn ratios compared to the control group (p < 0.05). Unlike the control group, concentrations of inflammatory cytokines, MT, Zn, and Ca correlated with each other in the PD, RA, and RAPD groups (p < 0.05). Additionally, comorbidity of PD and RA appears to have a cumulative immuno-pathological impact that warrants further investigation. This study suggests that, in addition to inflammatory cytokines, salivary MT and Zn could reflect the severity of PD with or without RA, hence providing an important biomarker for diagnosis.

Topics: Arthritis, Rheumatoid; Cytokines; Humans; Metallothionein; Periodontitis; Random Amplified Polymorphic DNA Technique; Zinc

It is now well accepted that an imbalance between the Th17 and regulatory T-cell responses is closely associated with the development of rheumatoid arthritis (RA). However, the precise regulatory mechanism for the differentiation of Th17 and Treg in RA is not well characterized. The present study showed that metallothionein-1 (MT-1), which is a low molecular weight protein that is involved in the detoxification of heavy metals and scavenging of free radicals, was upregulated in RA. Furthermore, the synovial inflammation and pathologic symptoms in collagen-induced arthritis and collagen antibody-induced arthritis mice were significantly suppressed when MT-1 was expressed intraarticularly. Further investigation revealed that MT-1 inhibited the differentiation of Th17 cells but enhanced that of Treg cells. Furthermore, it markedly decreased both STAT3 and RAR-related orphan receptor gamma t (RORγt) expression in vitro and in vivo. Collectively, our studies demonstrated that MT-1 might manifest as a protein involved in immunosuppression of RA pathogenesis by shifting Th17/Treg balance and may prove to be a potential therapeutic target for RA autoimmune diseases.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cell Differentiation; Humans; Lymphocyte Count; Male; Metallothionein; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Nuclear Receptor Subfamily 1, Group F, Member 3; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells

Zinc (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.. Cell/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.. Synoviocytes 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.. Zinc counteracts the deleterious effect of Cd by reducing its import and accumulation in the cell, without the reactivation of destructive pathways such as MMPs.

Topics: Arthritis, Rheumatoid; Biological Transport; Cadmium; Cell Proliferation; Cells, Cultured; Chronic Disease; Humans; Interleukin-17; Matrix Metalloproteinase 3; Metallothionein; Osteoarthritis; Synovial Membrane; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha; Zinc

The aim of this prospective multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis (RA).. We recruited patients with RA who were treated with tocilizumab for the first time, and determined therapeutic responses at 6 months. In the training cohort (n = 40), gene expression in peripheral blood mononuclear cells (PBMCs) at baseline was analyzed using genome-wide DNA microarray, with 41,000 probes derived from 19,416 genes. In the validation cohort (n = 20), expression levels of the candidate genes in PBMCs at baseline were determined using real-time quantitative polymerase chain reaction (qPCR) analysis.. We identified 68 DNA microarray probes that showed significant differences in signal intensity between nonresponders and responders in the training cohort. Nineteen putative genes were selected, and a significant correlation between the DNA microarray signal intensity and the qPCR relative expression was confirmed in 15 genes. In the validation cohort, a significant difference in relative expression between nonresponders and responders was reproduced for 3 type I interferon response genes (IFI6, MX2, and OASL) and MT1G. Receiver operating characteristic curve analysis of models incorporating these genes showed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the validation cohort.. Using genome-wide DNA microarray analyses, we identified candidate biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with RA. These findings suggest that type I interferon signaling and metallothioneins are involved in the pathophysiology of RA.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Biomarkers; Case-Control Studies; Female; Gene Expression Regulation; Humans; Interferon Type I; Leukocytes, Mononuclear; Male; Metallothionein; Middle Aged; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Female; Humans; Interferon Type I; Leukocytes, Mononuclear; Male; Metallothionein; Oligonucleotide Array Sequence Analysis

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Female; Humans; Interferon Type I; Leukocytes, Mononuclear; Male; Metallothionein; Oligonucleotide Array Sequence Analysis

Rheumatoid arthritis is characterized by chronic inflammation of the synovial tissue. We examined the effect of interleukin (IL)-6 neutralization on the expression of cytochrome P450 or metallothionein-1/2 (metallothionein) during chronic phase inflammatory disease using rheumatoid arthritis model mice, human T-cell leukemia virus type I (HTLV-I) transgenic mice. Serum IL-6 concentrations of arthritis-developed HTLV-I transgenic mice were 129.9+/-26.1 pg/ml. Moreover, signal transducer and activator of transcription (STAT) 1/3 phosphorylations was observed in arthritic HTLV-I transgenic mouse livers. CYP3A11 mRNA was more strongly reduced by the development of arthritis in HTLV-I transgenic mouse livers as compared with CYP2C29 or CYP2E1 mRNAs. CYP3A protein and testosterone 6beta-hydroxylation activity also changed in a similar manner to the corresponding CYP3A11 mRNA level. On the other hand, metallothionein mRNA was significantly induced as compared with that of wild-type or non-arthritic mice. CYP3A suppression and metallothionein mRNA overexpression activity seen in the developed arthritic mice returned to the gene conditions of the non-arthritic HTLV-I transgenic mice by IL-6 antibody at 48 h after treatment. The present study has revealed that CYP3A11 and metallothionein expressions are affected by the release of IL-6 by arthritis and its systemic circulation, and neutralization of IL-6 recovered from the down-regulation of CYP3A11 mRNA and the induction of metallothionein mRNA in arthritic HTLV-I transgenic mice.

Topics: Animals; Arthritis, Rheumatoid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Human T-lymphotropic virus 1; Interleukin-6; Liver; Membrane Proteins; Metallothionein; Mice; Mice, Inbred BALB C; Mice, Transgenic; Phosphorylation; RNA, Messenger; STAT1 Transcription Factor; STAT3 Transcription Factor; Steroid Hydroxylases

Previously, we showed that gene expression of the rheumatoid arthritis-related antigen RA-A47, which is identical to human heat shock protein (HSP)47, was downregulated in chondrocytes by inflammatory cytokines such as TNFalpha. Associated with this phenomenon, RA-A47 appeared on the cell surface concomitant with upregulation of metabolic factors related to cartilage destruction. The upregulation of the metabolic factors could be achieved by downregulation of RA-A47 expression with ra-a47-specific anti-sense oligonucleotide. Here, we show that the enhanced surface expression of RA-A47 on a chondrocytic cell line, HCS-2/8 was also a direct result of RA-A47 downregulation by ra-a47 anti-sense oligonucleotide, independent of the cytokine effects. Moreover, cell-surface expression of CD9, a beta1 integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleotide-treated cells. The CD9 was colocalized with RA-A47 on the cell surface, where it may have affected integrin signaling. Furthermore, Annexin-V binding to the cell surface and the level of a number of apoptosis-related genes including caspase-9 were increased after ra-a47 anti-sense oligonucleotide treatment, suggesting that enhanced surface expression of RA-A47 and CD9 may be initiating apoptosis. Differential screening using a cDNA gene array showed induction of metallothionein-III and chemokine receptor CXCR4 and of factors of the Notch signaling pathway by the anti-sense treatment, but not by TNFalpha. Thus, here we show for the first time an alternative mechanism of inducing apoptosis by downregulating molecular chaperones, independent of the action of TNFalpha. The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheumatoid arthritis.

Topics: Annexin A5; Antigens, CD; Antigens, Surface; Apoptosis; Arthritis, Rheumatoid; Autoantibodies; Cartilage; Caspase 9; Caspases; Cell Line, Tumor; Cell Membrane; Chondrocytes; Down-Regulation; Gene Expression Regulation; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Humans; Integrins; Membrane Glycoproteins; Metallothionein; Molecular Chaperones; Oligoribonucleotides, Antisense; Protein Binding; Receptor, Notch2; Receptors, Cell Surface; Receptors, CXCR4; Serpins; Tetraspanin 29; Tumor Necrosis Factor-alpha

The expression of metallothionein, an intracellular heavy-metal-binding protein, and p-glycoprotein, an energy-dependent drug efflux pump, was examined to study the mechanism of cell resistance to gold sodium thiomalate (GST). THP-1, one of the monocyte-derived cell lines, was cultured for 6 months and resistance to 25 microg/ml of GST (GST-resistant cells) was thus induced. The GST-resistant cells were then cultured with bucillamine to examine the presence of cross-resistance. The intracellular GST concentration was examined by flameless atomic absorption spectroscopy. The cell viability was determined by the uptake of 3-4,5 dimethylthiazole-2,5 diphenyl tetrazolium bromide (MTT). The expression of p-glycoprotein was detected by Western blotting using monoclonal anti-p-glycoprotein antibody. The expression of metallothionein was detected using the indirect immunofluorescence technique. GST-resistant cells did not show any cross-resistance to bucillamine. The rate of cytoplasmic GST accumulation decreased in the GST-resistant cells, while the rate of GST efflux also decreased. The expression of p-glycoprotein in the GST-resistant cells was not significantly different from that in the cells not treated with GST. On the other hand, the GST-resistant cells showed a higher expression of metallothionein than cells not treated with GST. These findings suggest that the induced resistance to GST might partly be due to an induction of metallothionein.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line; Cysteine; Cytoplasm; Dose-Response Relationship, Drug; Drug Resistance; Fluorescent Antibody Technique, Indirect; Gold Sodium Thiomalate; Humans; Metallothionein; Monocytes; Sensitivity and Specificity

Metallothioneins (MTs) are low-molecular-weight cytosolic proteins, which are thought to participate in metal homeostasis and protection against metal toxicity and oxidative stress. MT synthesis can be induced by a variety of inflammatory mediators and antirheumatic drugs, and high levels of MT have been implicated in resistance of cells to some antirheumatic drugs. We studied the expression and localization of MT in synovial tissue samples from patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or osteoarthritis (OA) by quantitative immunohistochemistry. Immunostaining for MT was detected in a large number of intimal lining cells in most of the investigated synovial tissue samples (75%). In a smaller proportion of samples (42%), some of the fibroblast-like cells of the subsynovial layer were also MT positive. Immunostaining and double-staining experiments with antibodies against monocyte-, macrophage- and leucocyte-associated antigens suggested that most of the MT-positive cells were intimal fibroblast-like cells and subsynovial fibroblasts. However, there were no statistically significant differences in the intensity of staining for MT between the rheumatic diseases and OA at the single-cell level. Thus, MT is expressed in synovial tissue and may participate in homeostatic and protective functions. The interindividual variability in the expression of MT in synovial tissue may be related to the therapeutic efficacy of the gold compounds and chemotherapeutic antirheumatic drugs sequestered by MT.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; Arthritis; Arthritis, Psoriatic; Arthritis, Rheumatoid; Child; Female; Humans; Immunohistochemistry; Joint Diseases; Male; Membrane Glycoproteins; Metallothionein; Mice; Middle Aged; Muramidase; Osteoarthritis; Spondylitis, Ankylosing; Synovial Membrane

Metallothionein is a ubiquitous low molecular weight metalloprotein with powerful protective properties against oxygen radical-mediated cytotoxicity associated with inflammatory processes. In rheumatoid arthritis, the inflammatory damage to the synovium appears to be mediated by free radicals released by the high concentration of neutrophils found in the synovial fluid of the inflamed joint. Synovial tissue obtained during routine surgery on rheumatoid and non-rheumatoid joints was subjected to an indirect immunoperoxidase protocol for the immunolocalization of metallothionein using mouse monoclonal anti-metallothionein antibody E9, reactive against the two major isoforms of mammalian metallothionein. A layer of large dendritic-like cells situated subsynovially in the rheumatoid synovium stained very positively for the metalloprotein, both cytoplasmically and in their nuclei. These cells were not found in non-rheumatoid osteoarthritic or in undamaged synovial tissue associated with traumatic joint injury. An attempt was made to investigate their lineage using a series of antibody markers against epithelial cells, endothelial cells, smooth muscle, mesothelial cells, fibroblasts, neutrophils, dermal dendrocytes, macrophages, low and high molecular weight cytokeratin as well as a cell proliferation marker. From our results, it is suggested that these metallothionein-positive cells are probably myofibroblasts similar to the highly motile cells present in granulation tissue. They may originate from perivascular areas of synovium and their movement into the inflamed synovium may reflect the cytoprotective role of metallothionein acting as a free radical scavenger against oxidative damage.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Arthritis, Rheumatoid; Biomarkers; Factor XIII; Humans; Immunohistochemistry; Metallothionein; Osteoarthritis; Synovial Membrane

The efficacy of gold treatment in rheumatoid arthritis is hampered by toxicity, most prevalent in early phases, and unresponsiveness which can only be assessed after more than 6 months on therapy. There is some evidence that more severe disease increases the likelihood of drug resistance. No data indicate an altered pharmacokinetics in resistant individuals, although increased dosage of parenteral gold has been claimed effective in uncontrolled studies. Exposure to metals induces cell adaption and resistance in both prokaryotic and eukaryotic cell lines. In particular this has been shown for gold chloride, sodium aurothiomalate and auranofin. Auranofin induces increased synthesis of metallothionein, a low molecular weight cystein-rich peptide with metal-binding and -homeostatic properties. Thus there is experimental evidence suggesting cellular adaptation as a potential mechanism for gold resistance. However, with the possible exception of auranofin, the nature of the processes remains unknown.

Topics: Animals; Arthritis, Rheumatoid; Bacteria; Drug Resistance; Gold; Humans; Metallothionein

Radioimmunoassay (RIA) and reversed-phase high-pressure liquid chromatography (HPLC) were used to investigate gold-binding proteins of possible metallothionein (MT) nature occurring upon auranofin exposure of cultured human cells. An epithelial cell line (HE) and two sub-strains were examined. The HEAF sub-strain had been made resistant to 2 mumole auranofin/l culture medium. The resistance was associated with the appearance of gold-binding substances with gel filtration characteristics like MT. The HE100 sub-strain had been made resistant to 100 mumole CdCl2/l and contained high amounts of cytosolic Cd-induced MT. In addition, cultured synovial fibroblasts, derived from normal (SN) and rheumatoid (SRA) synovial tissues, were investigated. Evidence was obtained by RIA that the low molecular weight (mol.wt. 6000-7000) gold-binding proteins occurring in the HEAF cells and SRA cells following auranofin exposure, were of MT nature. The relative amounts of MT in the epithelial cell lines were: HE:HEAF:HE100 = 1:18:100. The relative amounts in the synovial fibroblasts were: SN:SRA:SRA treated with auranofin = 1:3:10. The HPLC methods used were found suitable for isolation of Cd-MT in the HE100 cells, but not for the Au-MT in the HEAF cells. By HPLC, the Cd-MT in the HE100 cells was resolved into 3 MT-1 and 1 MT-2 iso-proteins exhibiting the amino acid composition typical of MT. Judged by HPLC, the MT in these cells constituted 0.4% of the cytosolic proteins.

Topics: Amino Acids; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Auranofin; Aurothioglucose; Cadmium; Cells, Cultured; Chromatography, Gel; Chromatography, High Pressure Liquid; Epithelium; Fibroblasts; Gold; Humans; Hydrogen-Ion Concentration; Metallothionein; Radioimmunoassay; Synovial Membrane

The molecular mechanisms of action of gold complexes in the treatment of rheumatoid arthritis are partially known, as are the mechanisms of action and potential utility of gold complexes in the treatment of neoplastic disease. In this paper, data relative to the mechanism of cytotoxicity and structure activity relationships are presented. Concepts of future research are also discussed.

Topics: Anti-Inflammatory Agents; Antibody Formation; Antineoplastic Agents; Arthritis, Rheumatoid; Auranofin; Aurothioglucose; Cell Survival; Cells, Cultured; DNA, Superhelical; Gold; Humans; Melanoma; Metallothionein; Structure-Activity Relationship

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis, Rheumatoid; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Humans; Metallothionein; Receptors, Drug; Structure-Activity Relationship; Tissue Distribution