Publications by authors named "Jingwu Zhang"

87 Publications

Coexistence of Superconductivity and Superhardness in Beryllium Hexaboride Driven by Inherent Multicenter Bonding.

J Phys Chem Lett 2016 Dec 17;7(23):4898-4904. Epub 2016 Nov 17.

Center for High Pressure Science and Technology Advanced Research , Beijing 100094, China.

Unique multicenter bonding in boron-rich materials leads to the formation of complex structures and intriguing properties. Here global structural searches are performed to unearth the structure of beryllium hexaboride (BeB) synthesized decades ago. Three BeB phases (α, β, and γ) were predicted to be stable at ambient and high pressures. The ground state at ambient pressure, α-BeB, consists of a strong and uniformly distributed covalent B-B network, which results in exceptional elastic properties and a hardness of 46 GPa comparable to γ-B. Even more surprisingly, α-BeB retains credible electron phonon coupling in the boron sublattice, and is predicted to be superconducting at 9 K. Above 4 GPa, β-BeB is stabilized with alternating boron slabs and triangular beryllium layers analogous to the structure of MgB. The β-BeB is predicted to be superconducting at 24 K, similar to Nb(Al,Ge). The γ-BeB is stable above 340 GPa. The understanding of intrinsic multicenter-bonding mechanism and related properties demonstrated in the very example of BeB provides new insights for the design of tunable multifunctional materials.
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http://dx.doi.org/10.1021/acs.jpclett.6b02444DOI Listing
December 2016

Diverse ruthenium nitrides stabilized under pressure: a theoretical prediction.

Sci Rep 2016 09 15;6:33506. Epub 2016 Sep 15.

Center for High Pressure Science and Technology Advanced Research, Beijing 100094, China.

First-principles calculations were performed to understand the structural stability, synthesis routes, mechanical and electronic properties of diverse ruthenium nitrides. RuN with a new I-4m2 symmetry stabilized by pressure is found to be energetically preferred over the experimental NaCl-type and ZnS-type ones. The Pnnm-RuN2 is found to be stable above 1.1 GPa, in agreement with the experimental results. Specifically, new stoichiometries like RuN3 and RuN4 are proposed firstly to be thermodynamically stable, and the dynamical and mechanical stabilities of the newly predicted structures have been verified by checking their phonon spectra and elastic constants. A phase transition from P4/mmm-RuN4 to C2/c-RuN4 is also uncovered at 23.0 GPa. Drawn from bonding and band structure analysis, P4/mmm-RuN4 exhibits semi-metal-like behavior and becomes a semiconductor for the high-pressure C2/c-RuN4 phase. Meanwhile the P21/c-RuN3 shows metallic feature. Highly directional covalent N-N and Ru-N bonds are formed and dominating in N-enriched Ru nitrides, making them promising hard materials.
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http://dx.doi.org/10.1038/srep33506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024155PMC
September 2016

Structural variety beyond appearance: high-pressure phases of CrB4 in comparison with FeB4.

Phys Chem Chem Phys 2016 Jan;18(4):2361-8

Center for High Pressure Science and Technology Advanced Research, Shanghai 201203, China. and Geophysical Laboratory, Carnegie Institution of Washington, 5251 Broad Branch Road NW, Washington, DC 20015, USA.

Employing particle swarm optimization (PSO) combined with first-principles calculations, we systemically studied high-pressure behaviors of hard CrB4. Our predictions reveal a distinct structural evolution under pressure for CrB4 despite having the same initial structure as FeB4. CrB4 is found to adopt a new P2/m structure above 196 GPa, another Pm structure at a pressure range of 261-294 GPa and then a Pmma structure beyond 294 GPa. Instead of puckering boron sheets in the initial structure, the high-pressure phases have planar boron sheets with different motifs upon compression. Comparatively, FeB4 prefers an I41/acd structure over 48 GPa with tetrahedron B4 units and a P213 structure above 231 GPa having equilateral triangle B3 units. Significantly, CrB4 exhibits persistent metallic behavior in contrast with the semiconducting features of FeB4 upon compression. The varied pressure response of hard tetraborides studied here is of importance for understanding boron-rich compounds and designing new materials with superlative properties.
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http://dx.doi.org/10.1039/c5cp06745fDOI Listing
January 2016

Reaction-activated palladium catalyst for dehydrogenation of substituted cyclohexanones to phenols and H without oxidants and hydrogen acceptors.

Chem Sci 2015 Aug 19;6(8):4674-4680. Epub 2015 May 19.

School of Pharmacy , East China University of Science and Technology , Meilong Road 130 , Shanghai 200237 , China . Email: ; ; Tel: +86-21-64250627.

It is widely believed that the dehydrogenation of organic compounds is a thermodynamically unfavorable process, and thus requires stoichiometric oxidants such as dioxygen and metal oxides or sacrificial hydrogen acceptors to remove the hydrogen from the reaction mixture to drive the equilibrium towards the products. Here we report a previously unappreciated combination of common commercial Pd/C and H which dehydrogenates a wide range of substituted cyclohexanones and 2-cyclohexenones to their corresponding phenols with high isolated yields, with H as the only byproduct. The reaction requires no oxidants or hydrogen acceptors because instead of removing the generated hydrogen with oxidants or hydrogen acceptors, we demonstrated it can be used as a cocatalyst to help power the reaction. This method for phenol synthesis manifests a high atom economy, and is inherently devoid of the complications normally associated with oxidative dehydrogenations.
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http://dx.doi.org/10.1039/c5sc01044fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667403PMC
August 2015

Copper-catalyzed aerobic oxidative coupling of aromatic alcohols and acetonitrile to β-ketonitriles.

Org Lett 2014 Jan 6;16(2):350-3. Epub 2014 Jan 6.

School of Pharmacy, East China University of Science and Technology , Meilong Road 130, Shanghai 200237, China.

A practical, convenient, and cheap copper-catalyzed aerobic oxidative coupling of aromatic alcohols and acetonitrile to β-ketonitriles has been developed. The green C-C bond formation involving the loss of two hydrogen atoms from the corresponding two carbons, respectively, unlocks opportunities for markedly different synthetic strategies.
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http://dx.doi.org/10.1021/ol403555nDOI Listing
January 2014

Formation of C=N bonds by the release of H2: a new strategy for synthesis of imines and benzazoles.

Org Biomol Chem 2013 Jun;11(23):3776-80

Department of Chemistry, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China.

A new strategy for synthesis of imines using the approach of release of H2 has been developed. This oxidant- and acceptor-free Pd/C catalysis protocol is further applied to synthesis of benzoxazoles, benzimidazoles, and benzothiazoles through a one-pot cascade reaction with notably high yields.
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http://dx.doi.org/10.1039/c3ob40388bDOI Listing
June 2013

Structural and relative stabilities, electronic properties and possible reactive routing of osmium and ruthenium borides from first-principles calculations.

Dalton Trans 2013 May;42(19):7041-50

Key Laboratory of Metastable Materials Science and Technology, College of Material Science and Engineering, Yanshan University, Qinhuangdao 066004, China.

First-principles calculations are employed to provide a fundamental understanding of the structural features and relative stability, mechanical and electronic properties and possible reactive route for osmium and ruthenium borides. The structural searches and calculations of the formation enthalpy identify a low-energy monoclinic phase for OsB3 with P2(1)/m symmetry, an orthorhombic phase for OsB4 with Pmmn symmetry, an orthorhombic phase for RuB3 with Pnma symmetry and a hexagonal phase for RuB4 with P63/mmc symmetry. Also, the structure transition at high pressure is also predicted for MB3 and MB4 (M = Os and Ru). Moreover, among the borides, orthorhombic RuB3 and OsB4 phases are predicted to be potential hard materials with estimated Vickers hardness values of 26.3 and 31.3 GPa, respectively. The analysis on the electronic properties and crystal orbital Hamilton population shows that the directional boron-boron networks, together with the strong metal-boron bonds, are responsible for their excellent mechanical properties. Relative enthalpy calculations with respect to possible constituents are also investigated to assess the prospects for phase formation and an attempt at high-pressure synthesis is suggested to obtain osmium and ruthenium tri- and tetra-borides.
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http://dx.doi.org/10.1039/c3dt32918fDOI Listing
May 2013

Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis.

Nat Med 2013 Mar 10;19(3):322-8. Epub 2013 Feb 10.

Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, and Department of Medicine, Guanghua Rheumatology Hospital, Shanghai, China.

Regulatory T (Treg) cells suppress autoimmune disease, and impaired Treg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis-derived Treg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor α (TNF-α), leading to impaired Treg cell function. Moreover, TNF-α-induced Treg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-γ (IFN-γ)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a TNF-α-specific antibody restored Treg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in Treg cells. Thus, TNF-α controls the balance between Treg cells and pathogenic TH17 and TH1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.
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http://dx.doi.org/10.1038/nm.3085DOI Listing
March 2013

TNF-α impairs differentiation and function of TGF-β-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway.

J Mol Cell Biol 2013 Apr 12;5(2):85-98. Epub 2012 Dec 12.

Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai, China.

Deficiency in the TGF-β-induced regulatory T (iTreg) cell differentiation is associated with compromised immune homeostasis and plays a key role in many autoimmune diseases. Therapeutic intervention to enhance in situ iTreg differentiation has become a promising treatment modality for autoimmune diseases. Here we describe that the development of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE) is associated with selective impairment of iTreg differentiation largely due to the increased production of TNF-α. The neutralization of TNF-α markedly increases iTreg differentiation, leading to the amelioration of EAE, whereas the depletion of iTreg cells abolishes the therapeutic effect of an anti-TNF-α antibody. The inhibition of iTreg differentiation by TNF-α is mediated through a signaling cascade involving the induction of TNF receptor II (TNFR2) expression and the activation of Akt. The activated Akt in turn interacts with Smad3, resulting in the inhibition of TGF-β-induced Smad3 phosphorylation and consequently the reduction of p-Smad3 results in the decreased binding to the specific binding site of the foxp3 promoter, and finally foxp3 transcription itself. Interestingly, this regulatory pathway is iTreg cell specific as TNF-α does not activate Akt in naturally occurring regulatory T cells, therefore conferring a selective effect of TNF-α and its antagonism on iTreg cells. The study sheds new light on the critical role and underlying mechanism of TNF-α in the regulation of iTreg differentiation and provides a novel rationale for TNF-α antagonistic therapy for autoimmune diseases.
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http://dx.doi.org/10.1093/jmcb/mjs063DOI Listing
April 2013

Does the real ReN2 have the MoS2 structure?

Phys Chem Chem Phys 2013 Jan 16;15(1):183-7. Epub 2012 Nov 16.

Key Laboratory of Metastable Materials Science and Technology, College of Material Science and Engineering, Yanshan University, Qinhuangdao, 066004, China.

Rhenium nitride (ReN(2)) with the hexagonal MoS(2) structure was recently synthesized by metathesis reaction under high pressure. Here the calculated elastic and thermodynamic stabilities and chemical bonding show that the MoS(2) phase is unstable based on first-principles calculations. Meanwhile, the MoS(2)-type ReN(2) compound may be stabilized by nitrogen-vacancies from X-ray diffraction and supercell calculations. Structure searches identify a monoclinic C2/m phase for ReN(2), which is energetically more stable than previous predictions and MoS(2) structure over a wide range of pressures. Above 130 GPa, a tetragonal P4/mbm phase becomes favorable from enthalpy calculations. Both phases have superior mechanical properties, and their syntheses would have important applications fundamentally and technologically.
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http://dx.doi.org/10.1039/c2cp43010jDOI Listing
January 2013

Drug targets in the cytokine universe for autoimmune disease.

Trends Immunol 2013 Mar 29;34(3):120-8. Epub 2012 Oct 29.

Department of Neuroimmunology, GlaxoSmithKline Research and Development Center, Shanghai, China.

In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders.
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http://dx.doi.org/10.1016/j.it.2012.10.003DOI Listing
March 2013

Regulatory immune responses induced by IL-1 receptor antagonist in rheumatoid arthritis.

Mol Immunol 2011 Oct 22;49(1-2):290-6. Epub 2011 Sep 22.

Department of Immunology, Institutes of Medical Sciences, Shanghai JiaoTong University School of Medicine, Shanghai institute of Immunology, Shanghai, PR China.

Anakinra, a human recombinant IL-1 receptor antagonist, is approved for the treatment of RA. In this study, 12 patients received the placebo plus MTX treatment, 38 patients received Anakinra combined with MTX treatment. Compared with the placebo plus MTX group, serum levels of IL-17, IFN-γ, IL-21 and IL-1β significantly decreased, the percentages of Th17 cells and Th1 cells were lower and the percentage of Treg cells was higher after receiving Anakinra combined with MTX treatment. The observed regulatory immune responses collectively correlated with clinical improvement in treated patients. A substantial response, ACR 20 at 24 w were consistent with those at 12 w, 16 w and 20 w, and was accompanied by a marked improvement in RA related laboratory parameters. The study reveals that the combination of Anakinra and MTX is safe and well tolerated, which induces regulatory immune responses and significantly provides greater clinical benefit than the placebo plus MTX group.
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http://dx.doi.org/10.1016/j.molimm.2011.08.020DOI Listing
October 2011

Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease.

Immunity 2011 Aug 11;35(2):273-84. Epub 2011 Aug 11.

Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.

Neural progenitor cell (NPC) therapy is considered a promising treatment modality for multiple sclerosis (MS), potentially acting through neural repair. Here, we showed that intravenous administration of NPCs ameliorated experimental autoimmune encephalomyelitis (EAE) by selectively inhibiting pathogenic T helper 17 (Th17) cell differentiation. Leukemia inhibitory factor (LIF) produced by NPCs was responsible for the observed EAE suppression. Through the inducible LIF receptor expression, LIF inhibited the differentiation of Th17 cells in EAE mice and that from MS subjects. At the molecular level, LIF exerted an opposing effect on interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation required for Th17 cell differentiation by triggering a signaling cascade that activated extracellular signal-regulated MAP kinase (ERK) and upregulated suppressor of cytokine signaling 3 (SOCS3) expression. This study reveals a critical role for LIF in regulating Th17 cell differentiation and provides insights into the mechanisms of action of NPC therapy in MS.
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http://dx.doi.org/10.1016/j.immuni.2011.06.011DOI Listing
August 2011

Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation.

J Clin Invest 2011 Feb 25;121(2):658-70. Epub 2011 Jan 25.

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Graduate School of CAS, Chinese Academy of Sciences, Shanghai, China.

Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, physically interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Additional analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.
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http://dx.doi.org/10.1172/JCI42974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026720PMC
February 2011

Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine.

J Immunol 2010 Aug 9;185(3):1855-63. Epub 2010 Jul 9.

Joint Immunology Laboratory, Institute of Health Sciences, Shanghai 200025, China.

Berberine (BBR), an isoquinoline alkaloid derived from plants, is widely used as an anti-inflammatory remedy in traditional Chinese medicine. In this study, we showed that BBR was efficacious in the amelioration of experimental autoimmune encephalomyelitis (EAE) through novel regulatory mechanisms involving pathogenic Th1 and Th17 cells. BBR inhibited differentiation of Th17 cells and, to a lesser degree, Th1 cells through direct actions on the JAK/STAT pathway, whereas it had no effect on the relative number of CD4(+)Foxp3(+) regulatory T cells. In addition, BBR indirectly influenced Th17 and Th1 cell functions through its effect on the expression and function of costimulatory molecules and the production of IL-6, which was attributable to the inhibition of NF-kappaB activity in CD11b(+) APCs. BBR treatment completely abolished the encephalitogenicity of MOG(35-55)-reactive Th17 cells in an adoptive transfer EAE model, and the same treatment significantly inhibited the ability of MOG(35-55)-reactive Th1 cells to induce EAE. This study provides new evidence that natural compounds, such as BBR, are of great value in the search for novel anti-inflammatory agents and therapeutic targets for autoimmune diseases.
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http://dx.doi.org/10.4049/jimmunol.0903853DOI Listing
August 2010

Role of osteopontin in synovial Th17 differentiation in rheumatoid arthritis.

Arthritis Rheum 2010 Oct;62(10):2900-8

Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai JiaoTong University School of Medicine, and Shanghai Institute of Immunology, Shanghai, China.

Objective: Osteopontin (OPN) that is aberrantly produced in rheumatoid synovium is thought to play an important role in rheumatoid arthritis (RA). This study was undertaken to investigate the role of OPN in the differentiation and accumulation of Th17 cells in rheumatoid synovium.

Methods: Peripheral blood mononuclear cells and purified CD4+ T cells derived from patients with RA or healthy controls were used to test the effect of OPN in vitro. Cytokine expression was determined by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Intracellular staining and flow cytometry were used to detect the percentages of Th17 cells and OPN receptors. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation.

Results: The levels of OPN correlated significantly with interleukin-17 (IL-17) production and the frequency of Th17 cells in the synovial fluid (SF) of RA patients. Endogenous OPN produced in RA SF was responsible for markedly increased production of IL-17 in T cells, which was blocked by OPN antibody. The effect of OPN in Th17 differentiation was mediated through a mechanism independent of the IL-6/STAT-3 pathway or other cytokines and specifically involved the OPN receptors CD44 and CD29 and the transcription factor retinoic acid-related orphan receptor (ROR). Furthermore, OPN was found to induce H3 acetylation of the IL17A gene promoter, mainly through the CD44 binding domain in CD4+ T cells, allowing the interaction of the IL17A gene locus with ROR.

Conclusion: This study reveals new evidence of the critical role of OPN in Th17 differentiation in rheumatoid synovitis.
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http://dx.doi.org/10.1002/art.27603DOI Listing
October 2010

The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease.

Cell Mol Immunol 2010 May 12;7(3):182-9. Epub 2010 Apr 12.

Department of Neuroimmunology, GlaxoSmithKline Research and Development Center, Zhangjiang Pudong, Shanghai, China.

The propagation and regulation of an immune response is driven by a network of effector and regulatory T (Treg) cells. The interplay of effector T and Treg cells determines the direction of the immune response towards inflammation or its resolution in an autoimmune disease setting. In autoimmune diseases, this interplay shifts the balance in favor of the development of autoreactive effector T cells, resulting in inflammatory pathology. The objective of an effective therapeutic approach for autoimmune disease is to restore this balance. In this review, we describe the characteristics and development of pathogenic T helper 1 (Th1) and Th17 cells and the beneficial Treg cells in autoimmune diseases and the crucial roles of the cytokine milieu in influencing the balance of these T-cell subsets. Given the importance of cytokines, we discuss current immunotherapeutic strategies using cytokine or cytokine receptor antibodies for the treatment of autoimmune diseases.
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http://dx.doi.org/10.1038/cmi.2010.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002916PMC
May 2010

High doses of alpha-galactosylceramide potentiate experimental autoimmune encephalomyelitis by directly enhancing Th17 response.

Cell Res 2010 Apr 19;20(4):480-91. Epub 2010 Jan 19.

Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chong Qing Road, Shanghai 200025, China.

Alpha-galactosylceramide (alpha-GC) is widely known to activate invariant natural killer T (iNKT) cells to suppress myelin antigen-specific Th1 responses, protecting susceptible mice against experimental autoimmune encephalomyelitis (EAE). Here, we demonstrate an unexpected finding that high doses of alpha-GC exacerbated, rather than ameliorated, EAE. Similar results were observed when MOG(35-55)-specific T cells treated with high-dose alpha-GC were transferred into naïve syngeneic recipient mice. Further study showed that high doses of alpha-GC directly enhance the Th17 and Th1 response by activation of CD4(+)CD44(+) memory T cells through phosphorylation of STAT3 and activation of NF-kappaB. Unlike the activation of iNKT cells by low doses of alpha-GC, high doses of alpha-GC directly interacted with CD1d expressed on T cells and activated Th17 and Th1 cells. Furthermore, antigen-presenting cells (APCs) predominantly express CD1d1, whereas the majority of CD4(+) T cells express CD1d2. Knockdown of CD1d1 or CD1d2 gene expression by RNAi interfered with the activation of iNKT or Th17/Th1 cells, respectively. Therefore, alpha-GC treatment could improve or worsen EAE by engaging either APCs or Th17/Th1 cells depending on the dose used.
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http://dx.doi.org/10.1038/cr.2010.6DOI Listing
April 2010

IL-21 regulates Th17 cells in rheumatoid arthritis.

Hum Immunol 2010 Apr 28;71(4):334-41. Epub 2010 Jan 28.

Department of Immunology, Shanghai institute of Immunology, Shanghai, People's Republic of China.

IL-21 is a type I cytokine that like IL-2, IL-4, IL-7, IL-9, and IL-15 uses the common gamma chain of cytokine receptor. IL-21 has been shown to regulate the function of T cells, B cells, natural killer cells, and dendritic cells in immune responses. Although activated CD4(+) T cells produce IL-21, recent data suggest that novel subsets of effector T cells are the major producers in immune responses. In this study, we show that IL-21 expression correlates with the presence of Th17 cells in synovial fluid (SF) and peripheral blood in rheumatoid arthritis patients. Human CCR6+ CD4(+) T cells produce high levels of both IL-21 and IL-17. Similar to mouse T cells, IL-21 auto-regulates its own production in human CD4(+) T cells. IL-21 potently enhances Th17 proliferation and suppresses Foxp3 expression, leading to the expression of RORC. IL-21 is therefore an autocrine cytokine that regulates human Th17 cells in rheumatoid arthritis, and serves as a good target for treating this autoimmune disease.
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http://dx.doi.org/10.1016/j.humimm.2010.01.010DOI Listing
April 2010

Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease.

Nat Med 2010 Feb 10;16(2):191-7. Epub 2010 Jan 10.

Department of Neuroimmunology, GlaxoSmithKline Research and Development Center, Shanghai, China.

Interleukin-7 receptor (IL-7R) is genetically associated with susceptibility to multiple sclerosis. Here we describe that IL-7 is essential for survival and expansion of pathogenic T helper type 17 (T(H)17) cells in experimental autoimmune encephalomyelitis (EAE). IL-7 directly expanded effector T(H)17 cells in EAE and human T(H)17 cells from subjects with multiple sclerosis, whereas it was not required for T(H)17 differentiation. IL-7R antagonism rendered differentiated T(H)17 cells susceptible to apoptosis through the inhibition of Janus kinase-signal transducer and activator of transcription-5 (JAK-STAT5) pathway and altered expression of the prosurvival protein Bcl-2 and the proapoptotic protein Bax, leading to decreased severity of EAE. In contrast, T(H)1 and regulatory T (T(reg)) cells were less susceptible to or not affected by IL-7R antagonism in vivo. The selectivity was attributable to minimal expression of IL-7Ralpha in T(reg) cells and correlated with a high level of Socs1 (encoding suppressor of cytokine signaling-1) expression in T(H)1 cells. The study reveals a unique, previously undescribed role of IL-7-IL-7R in T(H)17 cell survival and expansion and has implications in the treatment of autoimmune disease.
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http://dx.doi.org/10.1038/nm.2077DOI Listing
February 2010

Thymic regulation of autoimmune disease by accelerated differentiation of Foxp3+ regulatory T cells through IL-7 signaling pathway.

J Immunol 2009 Nov 19;183(10):6135-44. Epub 2009 Oct 19.

Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai, China.

The exact role of adult thymus in autoimmune disease state is poorly understood. We show here that thymus regulated experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, as evidenced by loss of spontaneous recovery in thymectomized EAE mice. There was progressive enrichment for CD4 single-positive Foxp3(+) regulatory T cells in thymocytes during the course of EAE and they suppressed the disease when adoptively transferred. Thymus was shown to undergo an active process characterized by accelerated differentiation and proliferation of regulatory T (Treg) cells through a mechanism involving increased expression of IL-7 in stromal cells and dynamic expression of IL-7 receptor in thymic Treg cells. This process preceded EAE recovery and selectively affected Treg over non-Treg cells in the thymus, leading to increased output of thymic Treg cells and self-regulation of EAE. The study reveals a novel role of thymus in self-regulation of autoimmune condition.
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http://dx.doi.org/10.4049/jimmunol.0901576DOI Listing
November 2009

Regulatory and pro-inflammatory phenotypes of myelin basic protein-autoreactive T cells in multiple sclerosis.

Int Immunol 2009 Dec 11;21(12):1329-40. Epub 2009 Oct 11.

Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.

MBP-specific autoreactive T cells are considered pro-inflammatory T cells and thought to play an important role in the pathogenesis of multiple sclerosis (MS). Here, we report that MBP(83-99)-specific T cells generated from MS patients (n = 7) were comprised of pro-inflammatory and regulatory subsets of distinct phenotypes. The pro-inflammatory phenotype was characterized by high production of IFN-gamma, IL-6, IL-21 and IL-17 and low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and exhibited potent regulatory functions. The regulatory subset of MBP-specific T cells appeared to expand from the CD4(+)CD25(-) T-cell pool. Their FOXP3 expression was stable, independent of the activation state and it correlated with suppressive function and inversely with the production of IFN-gamma, IL-6, IL-21 and IL-17. In contrast, the phenotype and function of FOXP3(low) MBP-specific T cells were adaptive and dependent on IL-6. The higher frequency of FOXP3(high) MBP-specific T cells was observed when IL-6 was neutralized in the culture of PBMC with MBP. The study provides new evidence that MBP-specific T cells are susceptible to pro-inflammatory cytokine milieu and act as either pro-inflammatory or regulatory T cells.
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http://dx.doi.org/10.1093/intimm/dxp100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779831PMC
December 2009

Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS.

Eur J Immunol 2009 Sep;39(9):2525-36

Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA.

IFN-beta currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-beta on the regulation of OPN and IL-17 in MS patients. We found that IFN-beta used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4(+) T-cell level. In addition, IFN-beta inhibited the production of IL-17 and IL-21 in CD4(+) T cells. It has been described that IFN-beta suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-beta also acted directly on the CD4(+) T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-beta to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN(+) and IL-17(+) cells decreased in IFN-beta-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-beta treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-beta treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-beta in the treatment of MS.
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http://dx.doi.org/10.1002/eji.200838879DOI Listing
September 2009

Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1beta through the NF-kappaB and MAPK pathways in rheumatoid arthritis.

Arthritis Rheum 2009 Jul;60(7):1957-65

Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Objective: Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1beta (MIP-1beta), in RA.

Methods: Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation.

Results: The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP-1 and MIP-1beta in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP-1 or MIP-1beta in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP-1 or MIP-1beta, and this effect could be blocked by an anti-OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50-83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF-kappaB and MAPK pathways, involving the activation of IKKbeta, p38, and JNK.

Conclusion: These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP-1 and MIP-1beta.
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http://dx.doi.org/10.1002/art.24625DOI Listing
July 2009

Regulatory properties of copolymer I in Th17 differentiation by altering STAT3 phosphorylation.

J Immunol 2009 Jul;183(1):246-53

Institute of Health Sciences, Shanghai JiaoTong University School of Medicine, China.

Th17 and Th1 play an important role in multiple sclerosis for which copolymer I (COP-I) is a treatment option. We described here that the treatment effect of COP-I correlated with its unique regulatory properties on differentiation and survival of Th17 in experimental autoimmune encephalomyelitis mice, which was mediated through down-regulation of STAT3 phosphorylation. The effect of COP-I on Th17 differentiation required CD14(+) monocytes through IL-6 signaling as a key mediator to regulate STAT3 phosphorylation and subsequent RORgammat expression in Th17 cells. The observed effect was markedly dampened when monocytes were genetically deficient for IL-6. Similar regulatory properties of COP-I were demonstrated in human Th17 differentiation. The study revealed the differential regulatory roles and the novel mechanism of action of COP-I chiefly responsible for its treatment efficacy in experimental autoimmune encephalomyelitis and multiple sclerosis.
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http://dx.doi.org/10.4049/jimmunol.0900193DOI Listing
July 2009

A novel method for detection of phosphorylation in single cells by surface enhanced Raman scattering (SERS) using composite organic-inorganic nanoparticles (COINs).

PLoS One 2009 15;4(4):e5206. Epub 2009 Apr 15.

Department of Microbiology & Immunology, Stanford University, Stanford, California, United States of America.

Background: Detection of single cell epitopes has been a mainstay of immunophenotyping for over three decades, primarily using fluorescence techniques for quantitation. Fluorescence has broad overlapping spectra, limiting multiplexing abilities.

Methodology/principal Findings: To expand upon current detection systems, we developed a novel method for multi-color immuno-detection in single cells using "Composite Organic-Inorganic Nanoparticles" (COINs) Raman nanoparticles. COINs are Surface-Enhanced Raman Scattering (SERS) nanoparticles, with unique Raman spectra. To measure Raman spectra in single cells, we constructed an automated, compact, low noise and sensitive Raman microscopy device (Integrated Raman BioAnalyzer). Using this technology, we detected proteins expressed on the surface in single cells that distinguish T-cells among human blood cells. Finally, we measured intracellular phosphorylation of Stat1 (Y701) and Stat6 (Y641), with results comparable to flow cytometry.

Conclusions/significance: Thus, we have demonstrated the practicality of applying COIN nanoparticles for measuring intracellular phosphorylation, offering new possibilities to expand on the current fluorescent technology used for immunoassays in single cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666268PMC
July 2009

Spectral analysis of multiplex Raman probe signatures.

ACS Nano 2008 Nov;2(11):2306-14

Biomedical/Life Sciences, Digital Health Group, Intel Corporation, Santa Clara, California 95054, USA.

Raman nanoparticle probes are an emerging new class of optical labels for interrogation of physiological and pathological processes in bioassays, cells, and tissues. Although their unique emission signatures are ideal for multiplexing, the full potential of these probes has not been realized because conventional analysis methods are inadequate. We report a novel spectral fitting method that exploits the entire spectral signature to quantitatively extract individual probe signals from multiplex spectra. We evaluate the method in a series of multiplex assays using unconjugated and antibody-conjugated composite organic-inorganic nanoparticles (COINs). Results show sensitive multiplex detection of small signals (<2% of total signal) and similar detection limits in corresponding 4-plex and singlet plate binding assays. In a triplex assay on formalin-fixed human prostate tissue, two antibody-conjugated COINs and a conventional fluorophore are used to image expression of prostate-specific antigen, cytokeratin-18, and DNA. The spectral analysis method effectively removes tissue autofluorescence and other unknown background, allowing accurate and reproducible imaging (area under ROC curve 0.89 +/- 0.03) at subcellular spatial resolution. In all assay systems, the error attributable to spectral analysis constitutes
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http://dx.doi.org/10.1021/nn800243gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662378PMC
November 2008

Induction of CD4+CD25+Foxp3+ regulatory T cell response by glatiramer acetate in type 1 diabetes.

Cell Res 2009 May;19(5):574-83

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of CAS, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031, China.

Glatiramer acetate (GA) is an immunomodulatory peptide drug used to treat multiple sclerosis. Its treatment effect has been expanded to other autoimmune conditions such as uveoretinitis, inflammatory bowel disease, graft rejection and hepatic fibrosis. Here, we report that GA was effective in altering the clinical course of diabetes in cyclophosphamide (CY)-potentiated non-obese diabetic (CY-NOD) mice. Treatment with GA significantly reduced the diabetic rate in the mice and ameliorated insulitis, which coincided with increased CD4+CD25+Foxp3+ T cell response in treated mice. GA treatment led to increased expression of transcription factor Foxp3 and elevated production of interleukin-4 (IL-4) both in vivo and in vitro. It was evident that the effect of GA on up-regulation of Foxp3 was mediated partially through IL-4. IL-4 was found to maintain Foxp3 expression and regulatory function of CD4+CD25+ regulatory T cells (Tregs). This study provides new evidence that GA has treatment potential for type 1 diabetes through the induction of Tregs and that increased IL-4 production is partially responsible for the enhanced Treg's function in GA treatment.
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http://dx.doi.org/10.1038/cr.2009.12DOI Listing
May 2009

Structural stability and elastic and electronic properties of rhenium borides: first principle investigations.

Inorg Chem 2009 Jan;48(2):581-7

Department of Chemical Engineering, Yanshan University, Qinhuangdao 066004, China.

The structural stability and elastic and electronic properties of rhenium borides with different boron concentration are calculated systemically by means of first principle total energy calculations. The total energy calculations reveal that the WC-type structure is more energetically favorable for ReB and that the Re(2)P-type structure is more preferred for Re(2)B. The formation enthalpy of these borides have been studied by the solid synthesis routes. The calculated elastic properties indicate that Re(2)B(3), ReB, and Re(2)B phases are also potential hard materials. Although valence-electron density was often employed to evaluate elastic properties of materials, our calculations indicate that the bulk elastic properties of these borides are not direct correlation with their valence-electron density. The analysis of electronic structure, charge density distribution, and Mulliken overlap population provides further understanding of the elastic and superconductivity properties of these borides.
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http://dx.doi.org/10.1021/ic8019606DOI Listing
January 2009