Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Wu, Chuan; Pot, Caroline; Apétoh, Lionel; Thalhamer, Theresa; Murugaiyan, Gopal; Xiao, Sheng; Lee, Youjin; Rangachari, Manu; Yosef, Nir; Kuchroo, Vijay K.

doi:10.1073/pnas.1211776110

Cited by 48 publications

(63 citation statements)

References 30 publications

(31 reference statements)

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“…Although studies were previously performed in T cells, Mt1/Mt2-deficient mice were found to produce increased levels of Il10 following an immune challenge with anti-CD3/CD28. 59 Still, the role of metallothionein genes during immune challenges and inflammation are not fully elucidated, and low expression of Mt1 supports the proinflammatory nature of the response at the measured time-point. 60 Direct association in the literature between macrophages and the underexpressed gene Ptprcap was less clear, although it has been found in the monocyte precursors to macrophages.…”

Section: Discussionmentioning

confidence: 98%

Analytical workflow profiling gene expression in murine macrophages

Nixon

González-Peña

Lawson

et al. 2015

J. Bioinform. Comput. Biol.

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Comprehensive and simultaneous analysis of all genes in a biological sample is a capability of RNA-Seq technology. Analysis of the entire transcriptome benefits from summarization of genes at the functional level. As a cellular response of interest not previously explored with RNA-Seq, peritoneal macrophages from mice under two conditions (control and immunologically challenged) were analyzed for gene expression differences. Quantification of individual transcripts modeled RNA-Seq read distribution and uncertainty (using a Beta Negative Binomial distribution), then tested for differential transcript expression (False Discovery Rate-adjusted p-value < 0.05). Enrichment of functional categories utilized the list of differentially expressed genes. A total of 2079 differentially expressed transcripts representing 1884 genes were detected. Enrichment of 92 categories from Gene Ontology Biological Processes and Molecular Functions, and KEGG pathways were grouped into 6 clusters. Clusters included defense and inflammatory response (Enrichment Score = 11.24) and ribosomal activity (Enrichment Score = 17.89). Our work provides a context to the fine detail of individual gene expression differences in murine peritoneal macrophages during immunological challenge with high throughput RNA-Seq.

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Section: Discussionmentioning

confidence: 98%

Analytical workflow profiling gene expression in murine macrophages

Nixon

González-Peña

Lawson

et al. 2015

J. Bioinform. Comput. Biol.

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“…MTs play diverse roles in metal detoxification, antioxidation, regulation of Zn 2+ -dependent proteins, immune defence and cell differentiation 29 30. Notably, MTs regulate cellular Zn 2+ levels, and impaired Zn 2+ homoeostasis is implicated in the pathophysiology of aging and various diseases 31 32.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis

et al. 2016

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ObjectiveThe zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis.MethodsExperimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL).ResultsMTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.ConclusionsMTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.

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“…Thus, both STAT1 and STAT3 are involved in IL-10 production ( Figure 3 ). In contrast to the positive regulators, metallothioneins can inhibit Tr1 generation by inhibiting phosphorylation of STAT1 and STAT3 [53]. Besides increasing the production of IL-10 by Tr1, IL-27 can induce IL-10 production in other activated T cell subsets, including Th1, Th2, Th17, and Treg [13, 50, 54].…”

Section: Influence Of Il-27 On T Cells and B Cellsmentioning

confidence: 99%

IL-27-induced modulation of autoimmunity and its therapeutic potential

Meka

Venkatesha

Dudics

et al. 2015

Autoimmunity Reviews

147

130

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Interleukin-27 (IL-27) is a new member of the IL-12 family. It is produced by activated antigen-presenting cells and plays an important role in the regulation of CD4+ T cell differentiation and immune response. IL-27 activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways. Several studies have revealed that IL-27 promotes the differentiation of Th1 and Tr1, but inhibits Th2, Th17, and Treg cells. However, a few studies have shown an opposite effect on certain T cell subsets, such as Treg. IL-27 displays both pro- and anti- inflammatory activities in different autoimmune diseases. Here, we have discussed the role of IL-27 in rheumatoid arthritis, multiple sclerosis, colitis, lupus, psoriasis, type 1 diabetes, and uveitis. Most of this information is derived from experimental models of these autoimmune diseases. The mechanistic basis of the dual role of IL-27 in inflammation and autoimmunity is still not fully defined. In general, the pro-/ anti- inflammatory activity of IL-27 is influenced by the underlying immune effector pathways, the phase of the disease, the presence or absence of counter-regulatory cytokines/T cell subsets, and the tissue/cell type under study. Despite a spectrum of outcomes in various autoimmune diseases, mostly anti-inflammatory and immunomodulatory effects of IL-27 have been observed in this category of diseases. Accordingly, IL-27 represents a novel, promising target/agent for the treatment of autoimmune diseases.

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Metallothioneins negatively regulate IL-27–induced type 1 regulatory T-cell differentiation

Cited by 48 publications

References 30 publications

Analytical workflow profiling gene expression in murine macrophages

Analytical workflow profiling gene expression in murine macrophages

Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis

IL-27-induced modulation of autoimmunity and its therapeutic potential

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