149 results on '"Xu, Damo"'
Search Results
102. A Novel Pathway Regulating Lipopolysaccharide-Induced Shock by ST2/T1 Via Inhibition of Toll-Like Receptor 4 Expression
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Sweet, Matthew J., primary, Leung, Bernard P., additional, Kang, Daiwu, additional, Sogaard, Morten, additional, Schulz, Kerstin, additional, Trajkovic, Vladimir, additional, Campbell, Carol C., additional, Xu, Damo, additional, and Liew, Foo Y., additional
- Published
- 2001
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103. IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background
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Xu, Damo, primary, Trajkovic, Vladimir, additional, Hunter, David, additional, Leung, Bernard P., additional, Schulz, Kerstin, additional, Gracie, J. Alastair, additional, McInnes, Iain B., additional, and Liew, Foo Y., additional
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- 2000
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104. Th1 and Th2 CD4+ T Cells Provide Help for B Cell Clonal Expansion and Antibody Synthesis in a Similar Manner In Vivo
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Smith, Karen M., primary, Pottage, Lindsay, additional, Thomas, Elaine R., additional, Leishman, Andrew J., additional, Doig, Tamsin N., additional, Xu, Damo, additional, Liew, Foo Y., additional, and Garside, Paul, additional
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- 2000
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105. Expression of Th2 cytokines and the stable Th2 marker ST2L in the absence of IL-4 duringLeishmania major infection
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Kropf, Pascale, primary, Schopf, Lisa R., additional, Chung, Charles L., additional, Xu, Damo, additional, Liew, Foo Y., additional, Sypek, Joseph P., additional, and Müller, Ingrid, additional
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- 1999
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106. Protective Immune Responses Induced by Vaccination with an Expression Genomic Library ofLeishmania major
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Piedrafita, David, primary, Xu, Damo, additional, Hunter, David, additional, Harrison, Robert A., additional, and Liew, Foo Y., additional
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- 1999
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107. Immune effector mechanism in parasitic infections
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Liew, F.Y, primary, Xu, Damo, additional, and Ling Chan, W, additional
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- 1999
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108. Regulation of macrophage IL-12 synthesis byLeishmania phosphoglycans
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Piedrafita, David, primary, Proudfoot, Lorna, additional, Nikolaev, Andrei V., additional, Xu, Damo, additional, Sands, William, additional, Feng, Gui-Jie, additional, Thomas, Elaine, additional, Brewer, James, additional, Ferguson, Michael A. J., additional, Alexander, James, additional, and Liew, Foo Y., additional
- Published
- 1999
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109. Nitric oxide regulates Th1 cell development through the inhibition of IL-12 synthesis by macrophages
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Huang, Fang-Ping, primary, Niedbala, Wanda, additional, Wei, Xiao-Qing, additional, Xu, Damo, additional, Feng, Gui-jie, additional, Robinson, John H., additional, Lam, Charles, additional, and Liew, Foo Y., additional
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- 1998
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110. Cutting Edge: Mice Defective in Fas Are Highly Susceptible toLeishmania majorInfection Despite Elevated IL-12 Synthesis, Strong Th1 Responses, and Enhanced Nitric Oxide Production
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Huang, Fang-Ping, primary, Xu, Damo, additional, Esfandiari, Ehsan-O, additional, Sands, William, additional, Wei, Xiao-qing, additional, and Liew, Foo Y., additional
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- 1998
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111. Protective Effect on Leishmania major Infection of Migration Inhibitory Factor, TNF-α, and IFN-γ Administered Orally via Attenuated Salmonella typhimurium
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Xu, Damo, primary, McSorley, Stephen J., additional, Tetley, Lawrence, additional, Chatfield, Stephen, additional, Dougan, Gordon, additional, Chan, W. Ling, additional, Satoskar, Abhay, additional, David, John R., additional, and Liew, Foo Y., additional
- Published
- 1998
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112. Genetic vaccination against leishmaniasis
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Xu, Damo, primary and Liew, F.Y., additional
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- 1994
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113. Inhibition of nitric oxide synthesis by interleukin-4 may involve inhibiting the activation of protein kinase C epsilon
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Sands, William A., primary, Bulut, Vedat, additional, Severn, Alison, additional, Xu, Damo, additional, and Liew, Foo Y., additional
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- 1994
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114. Pre‐exposure of murine macrophages to lipopolysaccharide inhibits the induction of nitric oxide synthase and reduces leishmanicidal activity
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Severn, Alison, primary, Xu, Damo, additional, Doyle, Jacqueline, additional, Leal, Ludmila M. C., additional, O'Donnell, Catherine A., additional, Brett, Sara J., additional, Moss, David W., additional, and Liew, Foo Y., additional
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- 1993
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115. Repeated induction of nitric oxide synthase and leishmanicidal activity in murine macrophages
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Cunha, Fernando Q., primary, Assreuy, Jamil, additional, Xu, Damo, additional, Charles, Ian, additional, Liew, Foo Y., additional, and Moncada, Salvador, additional
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- 1993
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116. Expression and function of Toll-like receptor on T cells
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Xu, Damo, Komai-Koma, Mousa, and Liew, Foo Y.
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LYMPHOCYTES , *CELL membranes , *PATTERN perception , *NATURAL immunity , *T cell receptors - Abstract
Abstract: Toll is the founder of a group of pattern recognition receptors, which play a critical role in the innate immunity in Drosophila. At least 13 distinct Toll-like receptors (TLRs), recognising pathogen-associated molecular pattern (PAMPs), have now been identified in humans. Most investigations on TLRs have focused on cells of the innate system. We report here that naïve human T cells expressed high levels of cell surface TLR2 after activation by anti-T cell receptor (TCR) antibody and interferon-α. Activated cells produced elevated levels of cytokines in response to the TLR2 ligand, bacterial lipopeptide (BLP). Furthermore, CD4+CD45RO+ memory T cells from peripheral blood constitutively expressed TLR2 and produced IFNγ in response to BLP. BLP also markedly enhanced the proliferation and IFNγ production by CD45RO+ T cells in the presence of IL-2 or IL-15. Thus, TLR2 serves as a co-stimulatory receptor for antigen-specific T cell development and participates in the maintenance of T cell memory. This suggests that pathogens, via their PAMPs, may contribute directly to the perpetuation and activation of long term T cell memory in both antigen dependent and independent manner. [Copyright &y& Elsevier]
- Published
- 2005
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117. TLR2 is expressed on activated T cells as a costimulatory receptor.
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Komal-Koma, Mousa, Jones, Louise, Ogg, Graham S., Xu, Damo, and Liew, Foo Y.
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T cell receptors ,IMMUNOGLOBULINS ,PATHOGENIC microorganisms ,CELL proliferation ,LYMPHOCYTES ,PEPTIDES - Abstract
Toll is the founder of a group of pattern recognition receptors that play a critical role in the innate immunity in Drosophila. At least 10 distinct Toll-like receptors (TLRs), recognizing pathogen-associated molecular patterns, have now been identified in humans. Most investigations on TLRs have focused on cells of the innate system. We report here that naïve human T cells expressed high levels of cell- surface TLR2 after activation by anti-T cell receptor antibody and IFN-α. Activated cells produced elevated levels of cytokines in response to the TLR2 ligand, bacterial lipopeptide. Furthermore, CD4
+ CD45RO+ memory T cells from peripheral blood constitutively expressed TLR2 and produced IFN-γ in response to bacterial lipopeptide, which also markedly enhanced the proliferation and IFN-γ production by CD45RO+ T cells in the presence of 11-2 or IL-15. Thus, TLR2 serves as a costimulatory receptor for antigen-specific T cell development and participates in the maintenance of I cell memory. This suggests that pathogens, via their pathogen-associated molecular patterns, may contribute directly to the perpetuation and activation of long-term T cell memory in both antigen-dependent and independent manner. [ABSTRACT FROM AUTHOR]- Published
- 2004
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118. Expression of Th2 cytokines and the stable Th2 marker ST2L in the absence of IL-4 during Leishmania major infection.
- Author
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Kropf, Pascale, Schopf, Lisa R., Chung, Charles L., Xu, Damo, Liew, Foo Y., Sypek, Joseph P., and Müller, Ingrid
- Published
- 1999
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- View/download PDF
119. Effects of nitric oxide on the induction and differentiation of Th1 cells.
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Niedbala, Wanda, Wei, Xiao-Qing, Piedrafita, David, Xu, Damo, and Liew, Foo Yew
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- 1999
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120. Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans.
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Piedrafita, David, Proudfoot, Lorna, Nikolaev, Andrei V., Xu, Damo, Sands, William, Feng, Gui-Jie, Thomas, Elaine, Brewer, James, Ferguson, Michael A. J., Alexander, James, and Liew, Foo Y.
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- 1999
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121. Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells.
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Taylor-Robinson, Andrew W., Liew, Foo Y., Severn, Alison, Xu, Damo, McSorley, Stephen J., Garside, Paul, Padron, Julio, and Phillips, R. Stephen
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- 1994
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122. ST2, an IL‐1R family member, attenuates inflammation and lethality after intestinal ischemia and reperfusion
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Fagundes, Caio T., Amaral, Flávio A., Souza, Adriano L. S., Vieira, Angélica T., Xu, Damo, Liew, Foo Y., Souza, Danielle G., and Teixeira, Mauro M.
- Abstract
Ischemia reperfusion injury is characterized by local and systemic inflammation leading to considerable mortality. Previously, we have reported that soluble T1/ST2 (sST2), a member of the IL‐1 receptor gene family, inhibits LPS‐induced macrophage proinflammatory cytokine production. Here, we report the therapeutic effect of sST2‐Fc in a murine model of intestinal ischemia reperfusion‐induced injury. Administration of sST2‐Fc fusion protein i.v., 10 min before reperfusion, reduced the production of TNF‐α dose‐dependently in the intestine and in the lungs. The sST2‐Fc treatment with the highest dose (100 μg) resulted in inhibited vascular permeability, neutrophilia, and hemorrhage in the intestine and the lungs compared with controls treated with normal IgG. This was associated with down‐regulated tissue levels of proinflammatory cytokines, markedly reduced serum TNF‐α levels, and increased survival of mice from the sST2‐Fc‐treated group after ischemia and reperfusion injury. The beneficial effect of sST2‐Fc treatment was associated with elevated IL‐10 production in intestine and lung. sST2‐Fc was not able to prevent the inflammatory response associated with intestinal ischemia and reperfusion in IL‐10‐deficient mice, suggesting that sST2 exerts its anti‐inflammatory effect in a IL‐10‐dependent manner. These results also demonstrate that sST2‐Fc may provide a novel, complementary approach in treating ischemic reperfusion injury.
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- 2007
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123. IL-10-producing regulatory B cells induced by IL-33 (BregIL-33) effectively attenuate mucosal inflammatory responses in the gut.
- Author
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Sattler, Susanne, Ling, Guang-Sheng, Xu, Damo, Hussaarts, Leonie, Romaine, Andreas, Zhao, Hongzhi, Fossati-Jimack, Liliane, Malik, Talat, Cook, H. Terence, Botto, Marina, Lau, Yu-Lung, Smits, Hermelijn H., Liew, Foo Y., and Huang, Fang-Ping
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INFLAMMATORY bowel disease treatment , *LABORATORY mice , *B cells , *INTERLEUKIN-33 , *ALIMENTARY canal inflammation , *MUCOUS membrane diseases , *PHENOTYPES , *IMMUNOGLOBULIN M - Abstract
Abstract: Regulatory B cells (Breg) have attracted increasing attention for their roles in maintaining peripheral tolerance. Interleukin 33 (IL-33) is a recently identified IL-1 family member, which leads a double-life with both pro- and anti-inflammatory properties. We report here that peritoneal injection of IL-33 exacerbated inflammatory bowel disease in IL-10-deficient (IL-10−/−) mice, whereas IL-33-treated IL-10-sufficient (wild type) mice were protected from the disease induction. A phenotypically unconventional subset(s) (CD19+CD25+CD1dhiIgMhiCD5-CD23-Tim-1-) of IL-10 producing Breg-like cells (BregIL-33) was identified responsible for the protection. We demonstrated further that BregIL-33 isolated from these mice could suppress immune effector cell expansion and functions and, upon adoptive transfer, effectively blocked the development of spontaneous colitis in IL-10−/− mice. Our findings indicate an essential protective role, hence therapeutic potential, of BregIL-33 against mucosal inflammatory disorders in the gut. [Copyright &y& Elsevier]
- Published
- 2014
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124. KIF20A promotes the development of fibrosarcoma via PI3K-Akt signaling pathway.
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Jin, Zheng, Tao, Shuang, Zhang, Chao, Xu, Damo, and Zhu, Zhenhua
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FIBROSARCOMA , *CELLULAR signal transduction , *SARCOMA , *TUMOR growth , *LIVER metastasis - Abstract
Adult fibrosarcoma is an aggressive subtype of soft tissue sarcoma (STS), in which high expression of KIF20A indicates a poor prognosis. However, the precise role of KIF20A in fibrosarcoma progression remains unknown. In this study, we initially examined KIF20A expression and function in the human fibrosarcoma cell line HT-1080. The results showed that KIF20A was highly expressed in HT-1080, knockdown of KIF20A impaired cell proliferation, migration, invasion and induced G2/M arrest and cell apoptosis. Transcriptome study suggested that PI3K-Akt signal pathway was involved in these biological changes. We confirmed that PI3K-Akt and NF-κB signaling pathways were impaired after the down-regulation of KIF20A, which can be reversed by the Akt activator SC79 in HT-1080 in vitro. In a xenograft mouse model, knockdown of KIF20A inhibited tumor growth, Ki67 expression and liver metastasis. Taken together, our results suggested that KIF20A promoted fibrosarcoma progression via PI3K-Akt signaling pathway and might be a potential therapeutic target for fibrosarcoma. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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125. Interleukin-33 promoting Th1 lymphocyte differentiation dependents on IL-12.
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Komai-Koma, Mousa, Wang, Eryi, Kurowska-Stolarska, Mariola, Li, Dong, McSharry, Charles, and Xu, Damo
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INTERLEUKIN-33 , *LYMPHOCYTES , *LABORATORY mice , *CELL differentiation , *ANTIGEN presenting cells - Abstract
The pro-Th2 cytokine IL-33 is now emerging as an important Th1 cytokine-IFN-γ inducer in murine CD4 + T cells that is essential for protective cell-mediated immunity against viral infection in mice. However, whether IL-33 can promote human Th1 cell differentiation and how IL-33 polarizes Th1 cells is less understood. We assessed the ability of IL-33 to induce Th1 cell differentiation and IFN-γ production in vitro and in vivo . We report here that IL-33 alone had no ability in Th1 cell polarization. However it potentiated IL-12-mediated Th1 cell differentiation and IFN-γ production in TCR-stimulated murine and human CD4 + T cells in vitro and in vivo . IL-33 promoted Th1 cell development via MyD88 and synergized with IL-12 to enhance St2 and IL-12R expression in CD4 + T cells. These data therefore provide a novel mechanism for Th1 cell differentiation and optimal induction of a Type 1 response. Thus, IL-33 is capable of inducing IL-12-dependent Th1 cell differentiation in human and mouse CD4 + T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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126. Monophosphoryl lipid A directly regulates Th1 cytokine production in human CD4+ T-cells through Toll-like receptor 2 and 4.
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Komai-Koma, Mousa, Ji, Yuan, Cao, Hui, Liu, Zhigang, McSharry, Charles, and Xu, Damo
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CYTOKINES , *TOLL-like receptors , *IMMUNOLOGICAL adjuvants , *POLYMYXIN , *LIPIDS , *VACCINE development , *T cells - Abstract
The monophosphoryl lipid A (MPLA) is a detoxified LPS derivative and an emerging safe immune adjuvant in human vaccine development. The adjuvant MPLA promotes antigen-presenting cell (APC) function and preferentially induces a Th1 response following vaccination. However, the mechanism by which the MPLA detoxicates and exerts its adjuvants effect on T-cell, particualrly the Th1 response is unknown. We assessed the direct effects of MPLA on murine and human CD4+ T-cell proliferation and the profile of cytokine production ex vivo. We report that CD4+ T-cells only express functional TLR2 and TLR4 when activated by TCR stimulation, in particularly in the presence of IFNα. The activated T cells thereafter can respond directly to MPLA. MPLA does not affect T-cell proliferation in human T cells, but can induce a balanced Th1 cytokine profile in CD4+ T-cells by reducing the production of Th1 cytokines and enhancing the production of the regulatory cytokine IL-10. The MPLA-mediated regulatory effect on activated CD4+ T-cells is TLR2 and TLR4 dependent and can be abolished by the lipid A blocker polymyxin B. These data provide evidence, at least in part, for the safe induction of an appropriate level of Th1 response by adjuvant MPLA in human vaccine development. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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127. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice
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Mousa Komai-Koma, Damo Xu, Charles McSharry, Mariola Kurowska-Stolarska, Dong-Dong Li, Li-Li Zhang, Majid S. Jabir, Foo Y. Liew, Anne-Gaelle Besnard, Rodrigo Guabiraba, Gerard J. Graham, Li, Dong, Guabiraba, Rodrigo, McSharry, Charles, Xu, Damo, Institute of Infection, Immunity and Inflammation, University of Glasgow, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Umm Al-Qura University, University of Technology, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, King Abdulaziz University, Supported by Arthritis Research UK (AR UK 18912 to D.X.), the Medical Research Council UK, and the Wellcome Trust (to F.Y.L.), and Institut National de la Recherche Agronomique (INRA)-Université de Tours
- Subjects
mIL-33, Mature IL-33 ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,M1 macrophage, Classically activated macrophage ,chemistry.chemical_compound ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,alternatively activated macrophages ,Fibrosis ,Pulmonary fibrosis ,cytokine ,Immunology and Allergy ,Lymphocytes ,Lung ,qPCR, Quantitative PCR ,Mice, Knockout ,0303 health sciences ,Interleukin-13 ,medicine.diagnostic_test ,IL-33 ,lung fibrosis ,type 2 innate lymphoid cells ,Innate lymphoid cell ,respiratory system ,Arg1, Arginase 1 ,3. Good health ,ICOS, Inducible costimulator ,Cytokine ,medicine.anatomical_structure ,Mechanisms of Allergy and Clinical Immunology ,CT, Computed tomography ,FITC, Fluorescein isothiocyanate ,BAL, Bronchoalveolar lavage ,fibrose pulmonaire ,WT, Wild-type ,APC, Allophycocyanin ,Immunology ,BMDM, Bone marrow–derived macrophage ,macrophage ,Biology ,Bleomycin ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Macrophages, Alveolar ,medicine ,Animals ,Nos2, Inducible nitric oxide synthase 2 gene ,030304 developmental biology ,IPF, Idiopathic pulmonary fibrosis ,Interleukins ,M2 macrophage, Alternatively activated macrophage ,PE, Phycoerythrin ,Receptors, Interleukin ,Interleukin-33 ,medicine.disease ,Interleukin-1 Receptor-Like 1 Protein ,Mice, Inbred C57BL ,Bronchoalveolar lavage ,chemistry ,cellule lymphoide ,flIL-33, Full-length IL-33 ,ILC2, Type 2 innate lymphoid cell ,030215 immunology - Abstract
Background The initiation and regulation of pulmonary fibrosis are not well understood. IL-33, an important cytokine for respiratory diseases, is overexpressed in the lungs of patients with idiopathic pulmonary fibrosis. Objectives We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis. Methods Lung fibrosis was induced by bleomycin in wild-type or Il33r ( St2 ) −/− C57BL/6 mice treated with the recombinant mature form of IL-33 or anti–IL-33 antibody or transferred with type 2 innate lymphoid cells (ILC2s). The development and severity of fibrosis was evaluated based on lung histology, collagen levels, and lavage cytology. Cytokine and chemokine levels were quantified by using quantitative PCR, ELISA, and cytometry. Results IL-33 is constitutively expressed in lung epithelial cells but is induced in macrophages by bleomycin. Bleomycin enhanced the production of the mature but reduced full-length form of IL-33 in lung tissue. ST2 deficiency, anti–IL-33 antibody treatment, or alveolar macrophage depletion attenuated and exogenous IL-33 or adoptive transfer of ILC2s enhanced bleomycin-induced lung inflammation and fibrosis. These pathologic changes were accompanied, respectively, by reduced or increased IL-33, IL-13, TGF-β1, and inflammatory chemokine production in the lung. Furthermore, IL-33 polarized M2 macrophages to produce IL-13 and TGF-β1 and induced the expansion of ILC2s to produce IL-13 in vitro and in vivo . Conclusions IL-33 is a novel profibrogenic cytokine that signals through ST2 to promote the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function and enhancing profibrogenic cytokine production in an ST2- and macrophage-dependent manner.
- Published
- 2014
128. Selective production of IL-33-neutralizing autoantibody ameliorates asthma responses and severity.
- Author
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Ji Y, Wang E, Mohammed MT, Hameed N, Christodoulou MI, Liu X, Zhou W, Fang Z, Jia N, Yu H, Zhou Z, Sun Y, Huang SK, McSharry C, Zhong NS, Xiao X, Li J, and Xu D
- Subjects
- Humans, Female, Adult, Male, Middle Aged, Animals, Antibodies, Neutralizing immunology, Cytokines immunology, Cytokines blood, Mice, Young Adult, Immunoglobulin E immunology, Immunoglobulin E blood, Toll-Like Receptor 9 immunology, Toll-Like Receptor 9 agonists, Severity of Illness Index, Immunoglobulin G immunology, Immunoglobulin G blood, Asthma immunology, Autoantibodies immunology, Autoantibodies blood, Interleukin-33 immunology
- Abstract
Background: Natural anti-cytokine autoantibodies can regulate homeostasis of infectious and inflammatory diseases. The anti-cytokine autoantibody profile and relevance to the pathogenesis of asthma are unknown. We aim to identify key anti-cytokine autoantibodies in asthma patients, and reveal their immunological function and clinical significance., Methods: A Luciferase Immunoprecipitation System was used to screen serum autoantibodies against 11 key cytokines in patients with allergic asthma and healthy donors. The antigen-specificity, immunomodulatory functions and clinical significance of anti-cytokine autoantibodies were determined by ELISA, qPCR, neutralization assays and statistical analysis, respectively. Potential conditions for autoantibody induction were revealed by in vitro immunization., Results: Of 11 cytokines tested, only anti-IL-33 autoantibody was significantly increased in asthma, compare to healthy controls, and the proportion positive was higher in patients with mild-to-moderate than severe allergic asthma. In allergic asthma patients, the anti-IL-33 autoantibody level correlated negatively with serum concentration of pathogenic cytokines (e.g., IL-4, IL-13, IL-25 and IL-33), IgE, and blood eosinophil count, but positively with mid-expiratory flow FEF
25 - 75 %. The autoantibodies were predominantly IgG isotype, polyclonal and could neutralize IL-33-induced pathogenic responses in vitro and in vivo. The induction of the anti-IL-33 autoantibody in blood B-cells in vitro required peptide IL-33 antigen along with a stimulation cocktail of TLR9 agonist and cytokines IL-2, IL-4 or IL-21., Conclusions: Serum natural anti-IL-33 autoantibodies are selectively induced in some asthma patients. They ameliorate key asthma inflammatory responses, and may improve lung function of allergic asthma., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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129. Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles.
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Fang ZF, Wang ZN, Chen Z, Peng Y, Fu Y, Yang Y, Han HL, Teng YB, Zhou W, Xu D, Liu XY, Xie JX, Zhang JJ, and Zhong NS
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- Rats, Animals, Particulate Matter toxicity, Particulate Matter analysis, Vehicle Emissions toxicity, Rats, Sprague-Dawley, Air Pollutants toxicity, Air Pollutants analysis, Pulmonary Disease, Chronic Obstructive chemically induced
- Abstract
Background: Ambient fine particulate matter (PM
2.5 ) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5 , causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined., Results: Black carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures., Conclusions: DEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype., (© 2023. The Author(s).)- Published
- 2024
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130. The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ.
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Wei R, Han X, Li M, Ji Y, Zhang L, Christodoulou MI, Hameed Aga NJ, Zhang C, Gao R, Liu J, Fu J, Lu G, Xiao X, Liu X, Yang PC, McInnes IB, Sun Y, Gao P, Qin C, Huang SK, Zhou Y, and Xu D
- Subjects
- Humans, Up-Regulation, PPAR gamma metabolism, Cytokine Release Syndrome, Intracellular Signaling Peptides and Proteins metabolism, Cytokines metabolism, Sepsis
- Abstract
Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβ and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis., (© 2023. The Author(s), under exclusive licence to CSI and USTC.)
- Published
- 2023
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131. Attenuated airways inflammation and remodeling in IL-37a and IL-37b transgenic mice with an ovalbumin-induced chronic asthma.
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Cui L, Qin X, Fu T, Li C, Wang D, Hu Y, Li Y, Chen Y, Cui Y, Wang J, Yuan H, Lv Z, Liu J, Xu D, Wei R, Ying S, and Wang W
- Subjects
- Mice, Humans, Animals, Ovalbumin, Mice, Transgenic, Mice, Inbred C57BL, Lung metabolism, Inflammation pathology, Collagen adverse effects, Collagen metabolism, Hypertrophy metabolism, Hypertrophy pathology, Protein Isoforms, Disease Models, Animal, Mice, Inbred BALB C, Bronchoalveolar Lavage Fluid, Asthma metabolism, Respiratory Hypersensitivity metabolism, Respiratory Hypersensitivity pathology
- Abstract
Background: Asthma is a common chronic respiratory disease characterized by airways inflammation, hyperresponsiveness and remodeling. IL-37, an anti-inflammatory cytokine, consists of five splice isoforms, that is, a-e. Although it has been previously shown that recombinant human IL-37b is able to inhibit airway inflammation and hyperresponsiveness in animal models of asthma, the effects and difference of other IL-37 isoforms, such as IL-37a on features of asthma are unknown., Methods: Animal models of chronic asthma were established using IL-37a and IL-37b transgenic mice with C57BL/6J background and wild-type (WT) mice sensitized and nasally challenged with ovalbumin (OVA). Airway hyperresponsiveness was measured using FlexiVent apparatus, while histological and immunohistological stainings were employed to measure airways inflammation and remodeling indexes, including goblet cell metaplasia, mucus production, deposition of collagen, hypertrophy of airway smooth muscles and pulmonary angiogenesis., Results: Compared to WT mice, both IL-37a and IL-37b transgenic mice had significant reduced airway hyperresponsiveness and the declined total numbers of inflammatory cells, predominant eosinophils into airways and lung tissues. Furthermore, all features of airways remodeling, including degrees of mucus expression, collagen deposition, hypertrophy of smooth muscles, thickness of airways and neovascularization markedly decreased in IL-37 transgenic mice compared with OVA-treated WT mice., Conclusion: Our data suggest that both IL-37a and IL-37b isoforms are able to not only ameliorate airways inflammation and airways hyperresponsiveness, but also greatly reduce airways structural changes of animal models of chronic asthma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
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132. PF-431396 hydrate inhibition of kinase phosphorylation during adherent-invasive Escherichia coli infection inhibits intra-macrophage replication and inflammatory cytokine release.
- Author
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Li X, Ormsby MJ, Fallata G, Meikle LM, Walker D, Xu D, and Wall DM
- Subjects
- Humans, Animals, Mice, Phosphorylation, Cytokines, Inflammation, Focal Adhesion Kinase 2 genetics, Escherichia coli Infections
- Abstract
Adherent-invasive Escherichia coli (AIEC) have been implicated in the aetiology of Crohn's disease (CD). They are characterized by an ability to adhere to and invade intestinal epithelial cells, and to replicate intracellularly in macrophages resulting in inflammation. Proline-rich tyrosine kinase 2 (PYK2) has previously been identified as a risk locus for inflammatory bowel disease and a regulator of intestinal inflammation. It is overexpressed in patients with colorectal cancer, a major long-term complication of CD. Here we show that Pyk2 levels are significantly increased during AIEC infection of murine macrophages while the inhibitor PF-431396 hydrate, which blocks Pyk2 activation, significantly decreased intramacrophage AIEC numbers. Imaging flow cytometry indicated that Pyk2 inhibition blocked intramacrophage replication of AIEC with no change in the overall number of infected cells, but a significant reduction in bacterial burden per cell. This reduction in intracellular bacteria resulted in a 20-fold decrease in tumour necrosis factor α secretion by cells post-AIEC infection. These data demonstrate a key role for Pyk2 in modulating AIEC intracellular replication and associated inflammation and may provide a new avenue for future therapeutic intervention in CD.
- Published
- 2023
- Full Text
- View/download PDF
133. Deregulated Expression of IL-37 in Patients with Bladder Urothelial Cancer: The Diagnostic Potential of the IL-37e Isoform.
- Author
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Papasavva M, Amvrosiou S, Pilala KM, Soureas K, Christodoulou P, Ji Y, Stravodimos K, Xu D, Scorilas A, Avgeris M, and Christodoulou MI
- Subjects
- Humans, Biopsy, Prospective Studies, Urinary Bladder, Carcinoma, Transitional Cell, Urinary Bladder Neoplasms diagnosis, Urinary Bladder Neoplasms genetics
- Abstract
Cellular and molecular immune components play a crucial role in the development and perpetuation of human malignancies, shaping anti-tumor responses. A novel immune regulator is interleukin-37 (IL-37), already shown to be involved in the inflammation associated with the pathophysiology of many human disorders, including cancer. The interplay between tumor and immune cells is of great importance, especially for highly immunogenic tumors such as bladder urothelial carcinoma (BLCA). This study aimed to investigate the potential of IL-37 and its receptor SIGIRR (single immunoglobulin IL-1-related receptor) to serve as prognostic and/or diagnostic markers in patients with BLCA. To this end, a series of bioinformatics tools processing -omics datasets and specifically designed qPCR assays on human BLCA tumors and cancer cell lines were utilized. Bioinformatics analysis revealed that IL-37 levels correlate with BLCA tumor development and are higher in patients with longer overall survival. Furthermore, mutations on SIGIRR are associated with enhanced infiltration of the tumor by regulatory T cells and dendritic cells. Based on the qPCR validation experiments, BLCA epithelial cells express the IL-37c and IL-37e isoforms, while the latter is the predominant variant detected in tumor biopsies, also associated with higher grade and the non-muscle-invasive type. This is the first time, to the best of our knowledge, that IL-37 and SIGIRR levels have been assessed in BLCA tumor lesions, and associations with pathological and survival parameters are described, while a transcript variant-specific signature is indicated to have a diagnostic potential. These data strongly indicate the need for further investigation of the involvement of this cytokine and interconnected molecules in the pathophysiology of the disease and its prospective as a therapeutic target and biomarker for BLCA.
- Published
- 2023
- Full Text
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134. Expression, regulating mechanism and therapeutic target of KIF20A in multiple cancer.
- Author
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Jin Z, Peng F, Zhang C, Tao S, Xu D, and Zhu Z
- Abstract
Kinesin family member 20A (KIF20A) is a member of the kinesin family. It transports chromosomes during mitosis, plays a key role in cell division. Recently, studies proved that KIF20A was highly expressed in cancer. High expression of KIF20A was correlated with poor overall survival (OS). In this review, we summarized all the cancer that highly expressed KIF20A, described the role of KIF20A in cancer. We also organized phase I and phase II clinical trials of KIF20A peptides vaccine. All results indicated that KIF20A was a promising therapeutic target for multiple cancer., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)
- Published
- 2023
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135. Vanadium exposure exacerbates allergic airway inflammation and remodeling through triggering reactive oxidative stress.
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Tu W, Xiao X, Lu J, Liu X, Wang E, Yuan R, Wan R, Shen Y, Xu D, Yang P, Gong M, Gao P, and Huang SK
- Subjects
- Animals, Mice, Humans, Reactive Oxygen Species, Airway Remodeling, Antioxidants pharmacology, Cytokines metabolism, Inflammation complications, Pyroglyphidae, Dermatophagoides pteronyssinus, Oxidative Stress, Vanadium toxicity, Asthma etiology
- Abstract
Background: Metal components of environmental PM2.5 are associated with the exacerbation of allergic diseases like asthma. In our recent hospital-based population study, exposure to vanadium is shown to pose a significant risk for current asthma, but the causal relationship and its underlying molecular mechanisms remain unclear., Objective: We sought to determine whether vanadium co-exposure can aggravate house dust mite (HDM)-induced allergic airway inflammation and remodeling, as well as investigate its related mechanisms., Methods: Asthma mouse model was generated by using either vanadium pentoxide (V
2 O5 ) or HDM alone or in combination, in which the airway inflammation and remodeling was investigated. The effect of V2 O5 co-exposure on HDM-induced epithelial-derived cytokine release and oxidative stress (ROS) generation was also examined by in vitro analyses. The role of ROS in V2 O5 co-exposure-induced cytokine release and airway inflammation and remodeling was examined by using inhibitors or antioxidant., Results: Compared to HDM alone, V2 O5 co-exposure exacerbated HDM-induced airway inflammation with increased infiltration of inflammatory cells and elevated levels of Th1/Th2/Th17 and epithelial-derived (IL-25, TSLP) cytokines in the bronchoalveolar lavage fluids (BALFs). Intriguingly, V2 O5 co-exposure also potentiated HDM-induced airway remodeling. Increased cytokine release was further supported by in vitro analysis in human bronchial epithelial cells (HBECs). Mechanistically, ROS, particularly mitochondrial-derived ROS, was significantly enhanced in HBECs after V2 O5 co-exposure as compared to HDM challenge alone. Inhibition of ROS with its inhibitor N-acetyl-L-cysteine (NAC) and mitochondrial-targeted antioxidant MitoTEMPO blocked the increased epithelial release caused by V2 O5 co-exposure. Furthermore, vitamin D3 as an antioxidant was found to inhibit V2 O5 co-exposure-induced increased airway epithelial cytokine release and airway remodeling., Conclusions: Our findings suggest that vanadium co-exposure exacerbates epithelial ROS generation that contribute to increased allergic airway inflammation and remodeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tu, Xiao, Lu, Liu, Wang, Yuan, Wan, Shen, Xu, Yang, Gong, Gao and Huang.)- Published
- 2023
- Full Text
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136. Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma.
- Author
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Christodoulou P, Kyriakou TC, Boutsikos P, Andreou M, Ji Y, Xu D, Papageorgis P, and Christodoulou MI
- Abstract
Interleukin-37 (IL-37) is a relatively new IL-1 family cytokine that, due to its immunoregulatory properties, has lately gained increasing attention in basic and translational biomedical research. Emerging evidence supports the implication of this protein in any human disorder in which immune homeostasis is compromised, including cancer. The aim of this study was to explore the prognostic and/or diagnostic potential of IL-37 and its receptor SIGIRR (single immunoglobulin IL-1-related receptor) in human tumors. We utilized a series of bioinformatics tools and -omics datasets to unravel possible associations of IL-37 and SIGIRR expression levels and genetic aberrations with tumor development, histopathological parameters, distribution of tumor-infiltrating immune cells, and survival rates of patients. Our data revealed that amongst the 17 human malignancies investigated, IL-37 exhibits higher expression levels in tumors of lung adenocarcinoma (LUAD). Moreover, the expression profiles of IL-37 and SIGIRR are associated with LUAD development and tumor stage, whereas their high mRNA levels are favorable prognostic factors for the overall survival of patients. What is more, IL-37 correlates positively with a LUAD-associated transcriptomic signature, and its nucleotide changes and expression levels are linked with distinct infiltration patterns of certain cell subsets known to control LUAD anti-tumor immune responses. Our data indicate the potential value of IL-37 and its receptor SIGIRR to serve as biomarkers and/or immune-checkpoint therapeutic targets for LUAD patients. Further, the data highlight the urgent need for further exploration of this cytokine and the underlying pathogenetic mechanisms to fully elucidate its implication in LUAD development and progression.
- Published
- 2022
- Full Text
- View/download PDF
137. Network analysis for elucidating the mechanisms of Shenfu injection in preventing and treating COVID-19 combined with heart failure.
- Author
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Zhou W, Chen Z, Fang Z, and Xu D
- Subjects
- Humans, Medicine, Chinese Traditional, Molecular Docking Simulation, SARS-CoV-2, COVID-19, Drugs, Chinese Herbal, Heart Failure
- Abstract
Background: The emergence of the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to millions of infections and is exerting an unprecedented impact on society and economies worldwide. The evidence showed that heart failure (HF) is a clinical syndrome that could be encountered at different stages during the progression of COVID-19. Shenfu injection (SFI), a traditional Chinese medicine (TCM) formula has been widely used for heart failure therapy in China and was suggested to treat critical COVID-19 cases based on the guideline for diagnosis and treatment of COVID-19 (the 7th version) issued by National Health Commission of the People's Republic of China. However, the active components, potential targets, related pathways, and underlying pharmacology mechanism of SFI against COVID-19 combined with HF remain vague., Objective: To investigate the effectiveness and possible pharmacological mechanism of SFI for the prevention and treatment of COVID-19 combined with HF., Methods: In the current study, a network analysis approach integrating active compound screening (drug-likeness, lipophilicity, and aqueous solubility models), target fishing (Traditional Chinese Medicine Systems Pharmacology, fingerprint-based Similarity Ensemble Approach, and PharmMapper databases), compound-target-disease network construction (Cytoscape software), protein-protein interaction network construction (STRING and Cytoscape software), biological process analysis (STRING and Cytoscape plug-in Clue GO) and pathway analysis (Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis) was developed to decipher the active ingredients, potential targets, relevant pathways, and the therapeutic mechanisms of SFI for preventing and treating COVID-19 combined with HF., Results: Finally, 20 active compounds (DL ≥ 0.18, 1≤Alog P ≤ 5, and -5≤LogS ≤ -1) and 164 relevant targets of SFI were identified related to the development of COVID-19 combined with HF, which were mainly involved in three biological processes including metabolic, hemostasis, and cytokine signaling in immune system. The C-T-D network and reactome pathway analysis indicated that SFI probably regulated the pathological processes of heart failure, respiratory failure, lung injury, and inflammatory response in patients with COVID-19 combined with HF through acting on several targets and pathways. Moreover, the venn diagram was used to identify 54 overlapped targets of SFI, COVID-19, and HF. KEGG pathway enrichment analysis showed that 54 overlapped targets were highly enriched to several COVID-19 and HF related pathways, such as IL-17 signaling pathway, Th17 cell differentiation, and NF-kappa B signaling pathway., Conclusions: A comprehensive network analysis approach framework was developed to systematically elucidate the potential pharmacological mechanism of SFI for the prevention and treatment of SFI against COVID-19 combined with HF. The current study may not only provide in-depth understanding of the pharmacological mechanisms of SFI, but also a scientific basis for the application of SFI against COVID-19 combined with HF., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
138. Immunometabolism shapes B cell fate and functions.
- Author
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Fu Y, Wang L, Yu B, Xu D, and Chu Y
- Subjects
- B-Lymphocytes, Cell Differentiation, Homeostasis, Immunity, Metabolic Networks and Pathways
- Abstract
B lymphocyte-mediated humoral immune response is essential for protection against infectious diseases. Deeper research in B cell biology, particularly metabolism is required for the better understanding of its properties in homeostasis and in diseases. Emerging immunometabolism, including anabolism and catabolism, has tremendously impacts on immune cells from development to function and markedly advances our view on immunoregulation. Growing evidence suggests that the ultimate effect of intracellular metabolism on immune cell functions is not only influenced by the external stimuli but also by the balance of the different metabolic pathways. However, B cell immunometabolism is not deeply investigated like T cells. The complex development and differentiation processes of B cell subsets have left many untouched, but fundamental aspects in B cell metabolism. Available evidence demonstrated that the intracellular metabolism has the ubiquitous impact on B cell fate and function decisions at the transcriptional regulation and signal transduction processes. In this review, we update the recent development in the immunometabolism of B cells with the latest findings including the immune-metabolic steering on B cell development, differentiation, and function skewing, and emphasis on how immunometabolism landscape may shape B cell functions in metabolic, autoimmune, and inflammatory disorders. The metabolic interaction of B cells with other immune cells in disease context will also be discussed., (© 2022 John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
139. FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and contributes to allergic asthma progression.
- Author
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Wang SR, Hu RD, Ma M, You X, Cui H, He Y, Xu D, Zhao ZB, Selmi C, Eric Gershwin M, Li L, and Lian ZX
- Subjects
- Animals, Cell Differentiation, Forkhead Box Protein O1 genetics, Forkhead Box Protein O1 metabolism, Humans, Lymphocyte Activation, Mice, Positive Regulatory Domain I-Binding Factor 1, Asthma, Interleukin-10 metabolism
- Abstract
IL-10-producing B cells (B10) are involved in the prevention of autoimmune and allergic responses but its mechanisms remain poorly understood. We took advantage of the ovalbumin-induced asthma mouse model to demonstrate that the activity of FoxO1 is upregulated in lung B cells and correlates inversely with B10 cells, while showing decreased activity in ex vivo and in vitro induced B10 cells. We further observed that FoxO1 deficiency leads to increased frequency of B10 cells. These observations have in vivo clinical evidence, as B cell specific FoxO1 deficiency leads to reduced lung eosinophils and asthma remission in mice, and there are reduced regulatory B cells and increased FoxO1 activity in B cells of asthma patients. Single cell RNA-sequencing data demonstrated a negative correlation between the expression of Foxo1 and Il10 in B cells from the mouse spleen and lung and the human lung. For a biological mechanism, FoxO1 inhibits the expression of Prdm1, which encodes Blimp-1, a transcription factor of B10 cells. Our experimental evidence in both murine and human asthma demonstrates that FoxO1 is a negative regulator of B10 cell differentiation via negatively regulating Prdm1 and its expression in B cells contributes to allergic asthma disease., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)
- Published
- 2022
- Full Text
- View/download PDF
140. Correction: The signal pathways and treatment of cytokine storm in COVID-19.
- Author
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Yang L, Xie X, Tu Z, Fu J, Xu D, and Zhou Y
- Published
- 2021
- Full Text
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141. The signal pathways and treatment of cytokine storm in COVID-19.
- Author
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Yang L, Xie X, Tu Z, Fu J, Xu D, and Zhou Y
- Subjects
- Cytokine Release Syndrome virology, Cytokines, Humans, Respiratory Distress Syndrome therapy, Respiratory Distress Syndrome virology, COVID-19 therapy, Cytokine Release Syndrome therapy, Signal Transduction
- Abstract
The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.
- Published
- 2021
- Full Text
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142. IL-33: a key player in the development of iron-recycling red pulp macrophages.
- Author
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Xu D and Huang SK
- Subjects
- Macrophages, Spleen, Interleukin-33, Iron
- Published
- 2020
- Full Text
- View/download PDF
143. Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain.
- Author
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Zarpelon AC, Rodrigues FC, Lopes AH, Souza GR, Carvalho TT, Pinto LG, Xu D, Ferreira SH, Alves-Filho JC, McInnes IB, Ryffel B, Quesniaux VF, Reverchon F, Mortaud S, Menuet A, Liew FY, Cunha FQ, Cunha TM, and Verri WA Jr
- Subjects
- Animals, Astrocytes metabolism, Mice, Knockout, Microglia metabolism, Pain Threshold physiology, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction genetics, Signal Transduction physiology, Spinal Cord physiopathology, Alarmins metabolism, Hyperalgesia metabolism, Interleukin-33 metabolism, Neuralgia metabolism, Oligodendroglia metabolism, Spinal Cord metabolism
- Abstract
Neuropathic pain from injury to the peripheral and CNS represents a major health care issue. We have investigated the role of IL-33/IL-33 receptor (ST2) signaling in experimental models of neuropathic pain in mice. Chronic constriction injury (CCI) of the sciatic nerve induced IL-33 production in the spinal cord. IL-33/citrine reporter mice revealed that oligodendrocytes are the main cells expressing IL-33 within the spinal cord together with a minor expression by neurons, microglia. and astrocytes. CCI-induced mechanical hyperalgesia was reduced in IL-33R (ST2)(-/ -) mice compared with wild-type (WT) mice. Intrathecal treatment of WT mice with soluble IL-33 receptor (IL-33 decoy receptor) markedly reduced CCI-induced hyperalgesia. Consistent with these observations, intrathecal injection of IL-33 enhanced CCI hyperalgesia and induced hyperalgesia in naive mice. IL-33-mediated hyperalgesia during CCI was dependent on a reciprocal relationship with TNF-α and IL-1β. IL-33-induced hyperalgesia was markedly attenuated by inhibitors of PI3K, mammalian target of rapamycin, MAPKs (p38, ERK, and JNK), NF-κB, and also by the inhibitors of glial cells (microglia and astrocytes). Furthermore, targeting these signaling pathways and cells inhibited IL-33-induced TNF-α and IL-1β production in the spinal cord. Our study, therefore, reveals an important role of oligodendrocyte-derived IL-33 in neuropathic pain., (© FASEB.)
- Published
- 2016
- Full Text
- View/download PDF
144. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice.
- Author
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Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, Graham GJ, Kurowska-Stolarska M, Liew FY, McSharry C, and Xu D
- Subjects
- Animals, Fibrosis, Interleukin-1 Receptor-Like 1 Protein, Interleukin-13 genetics, Interleukin-13 immunology, Interleukin-33, Interleukins genetics, Lymphocytes immunology, Mice, Inbred C57BL, Mice, Knockout, Receptors, Interleukin genetics, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 immunology, Interleukins immunology, Lung immunology, Lung pathology, Macrophages, Alveolar immunology, Receptors, Interleukin immunology
- Abstract
Background: The initiation and regulation of pulmonary fibrosis are not well understood. IL-33, an important cytokine for respiratory diseases, is overexpressed in the lungs of patients with idiopathic pulmonary fibrosis., Objectives: We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis., Methods: Lung fibrosis was induced by bleomycin in wild-type or Il33r (St2)(-/-) C57BL/6 mice treated with the recombinant mature form of IL-33 or anti-IL-33 antibody or transferred with type 2 innate lymphoid cells (ILC2s). The development and severity of fibrosis was evaluated based on lung histology, collagen levels, and lavage cytology. Cytokine and chemokine levels were quantified by using quantitative PCR, ELISA, and cytometry., Results: IL-33 is constitutively expressed in lung epithelial cells but is induced in macrophages by bleomycin. Bleomycin enhanced the production of the mature but reduced full-length form of IL-33 in lung tissue. ST2 deficiency, anti-IL-33 antibody treatment, or alveolar macrophage depletion attenuated and exogenous IL-33 or adoptive transfer of ILC2s enhanced bleomycin-induced lung inflammation and fibrosis. These pathologic changes were accompanied, respectively, by reduced or increased IL-33, IL-13, TGF-β1, and inflammatory chemokine production in the lung. Furthermore, IL-33 polarized M2 macrophages to produce IL-13 and TGF-β1 and induced the expansion of ILC2s to produce IL-13 in vitro and in vivo., Conclusions: IL-33 is a novel profibrogenic cytokine that signals through ST2 to promote the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function and enhancing profibrogenic cytokine production in an ST2- and macrophage-dependent manner., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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145. Retraction. The cytokine interleukin-33 mediates anaphylactic shock.
- Author
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Pushparaj PN, Tay HK, H'ng SC, Pitman N, Xu D, McKenzie A, and Liew FY
- Published
- 2012
- Full Text
- View/download PDF
146. Direct recognition of LPS by human but not murine CD8+ T cells via TLR4 complex.
- Author
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Komai-Koma M, Gilchrist DS, and Xu D
- Subjects
- Animals, Antibodies immunology, Antibodies pharmacology, CD3 Complex immunology, Cell Proliferation drug effects, Gene Expression drug effects, Granzymes metabolism, Humans, Interferon-gamma metabolism, Interleukin-12 pharmacology, Leukocyte Common Antigens metabolism, Lipopolysaccharide Receptors genetics, Lipopolysaccharide Receptors metabolism, Lymphocyte Activation drug effects, Lymphocyte Antigen 96 genetics, Mice, Mice, Inbred C3H, Mice, Mutant Strains, Perforin metabolism, RNA, Small Interfering genetics, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Cytotoxic metabolism, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 genetics, Tumor Necrosis Factor-alpha metabolism, CD8-Positive T-Lymphocytes immunology, Lipopolysaccharides immunology, Toll-Like Receptor 4 immunology
- Abstract
LPS comprises a major PAMP and is a key target of the immune system during bacterial infection. While LPS can be recognised by innate immune cells via the TLR4 complex, it is unknown whether T lymphocytes, especially CD8(+) T cells are also capable of doing so. We report here that naive human CD8(+) T cells, after activation by TCR stimulation, express surface TLR4 and CD14. These activated CD8(+) T cells can then secrete high concentrations of IFN-gamma, granzyme and perforin in response to LPS. These effects can be specifically inhibited using siRNA for TLR4. Furthermore, LPS can synergize with IL-12 to polarize the CD8(+) T cells into cytotoxic T-cell 1 (Tc1) that produce IFN-gamma but not IL-4, with or without TCR activation. Moreover, CD8(+)CD45RO(+) memory T cells constitutively expressed TLR4 and markedly enhanced IFN-gamma production when stimulated with LPS. In contrast, activated murine CD8(+) T cells lack TLR4 and CD14 expression and fail to respond to LPS for proliferation and cytokine production. Thus, human but not murine CD8(+) T cells are able to directly recognise bacterial LPS via LPS receptor complex and TLR4 provides a novel signal for the activation of effector and memory human CD8(+) T cells.
- Published
- 2009
- Full Text
- View/download PDF
147. Direct and indirect role of Toll-like receptors in T cell mediated immunity.
- Author
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Xu D, Liu H, and Komai-Koma M
- Subjects
- Animals, Cell Differentiation physiology, Humans, Inflammation immunology, Ligands, Lymphocyte Activation, Signal Transduction physiology, T-Lymphocytes physiology, Immunity, Cellular physiology, Immunity, Innate physiology, T-Lymphocytes immunology, Toll-Like Receptors immunology
- Abstract
Toll-like receptors (TLRs) are pathogen-associated molecular patterns (PAMPs) recognition receptors that play an important role in protective immunity against infection and inflammation. They act as central integrators of a wide variety of signals, responding to diverse agonists of microbial products. Stimulation of Toll-like receptors by microbial products leads to signaling pathways that activate not only innate, but also adaptive immunity by APC dependent or independent mechanisms. Recent evidence revealed that TLR signals played a determining role in the skewing of naive T cells towards either Th1 or Th2 responses. Activation of Toll-like receptors also directly or indirectly influences regulatory T cell functions. Therefore, TLRs are required in both immune activation and immune regulation. Study of TLRs has significantly enhanced our understanding of innate and adaptive immune responses and provides novel therapeutic approaches against infectious and inflammatory diseases.
- Published
- 2004
148. TLR2 is expressed on activated T cells as a costimulatory receptor.
- Author
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Komai-Koma M, Jones L, Ogg GS, Xu D, and Liew FY
- Subjects
- Animals, Antigen-Presenting Cells immunology, Base Sequence, DNA Primers, Fetal Blood immunology, Flow Cytometry, Humans, Immunologic Memory, Infant, Newborn, Lymphocyte Activation immunology, Membrane Glycoproteins deficiency, Mice, Mice, Knockout, Polymerase Chain Reaction, Receptors, Cell Surface deficiency, Receptors, Cell Surface immunology, Toll-Like Receptor 2, Toll-Like Receptors, Membrane Glycoproteins genetics, Receptors, Cell Surface genetics, T-Lymphocytes immunology
- Abstract
Toll is the founder of a group of pattern recognition receptors that play a critical role in the innate immunity in Drosophila. At least 10 distinct Toll-like receptors (TLRs), recognizing pathogen-associated molecular patterns, have now been identified in humans. Most investigations on TLRs have focused on cells of the innate system. We report here that naïve human T cells expressed high levels of cell-surface TLR2 after activation by anti-T cell receptor antibody and IFN-alpha. Activated cells produced elevated levels of cytokines in response to the TLR2 ligand, bacterial lipopeptide. Furthermore, CD4(+)CD45RO(+) memory T cells from peripheral blood constitutively expressed TLR2 and produced IFN-gamma in response to bacterial lipopeptide, which also markedly enhanced the proliferation and IFN-gamma production by CD45RO(+) T cells in the presence of IL-2 or IL-15. Thus, TLR2 serves as a costimulatory receptor for antigen-specific T cell development and participates in the maintenance of T cell memory. This suggests that pathogens, via their pathogen-associated molecular patterns, may contribute directly to the perpetuation and activation of long-term T cell memory in both antigen-dependent and independent manner.
- Published
- 2004
- Full Text
- View/download PDF
149. CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4.
- Author
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Liu H, Hu B, Xu D, and Liew FY
- Subjects
- Animals, Antigens, CD, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CTLA-4 Antigen, Cells, Cultured, Colitis immunology, Colitis pathology, Disease Models, Animal, Female, Lymph Nodes cytology, Lymph Nodes immunology, Lymph Nodes transplantation, Male, Mice, Mice, Inbred BALB C, Mice, SCID, Spleen cytology, Spleen immunology, Spleen transplantation, Suppressor Factors, Immunologic physiology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Adoptive Transfer methods, Antigens, Differentiation physiology, CD4-Positive T-Lymphocytes transplantation, Colitis therapy, Interleukin-10 physiology, Receptors, Interleukin-2 biosynthesis, T-Lymphocyte Subsets transplantation, Transforming Growth Factor beta physiology
- Abstract
Regulatory T cells are critical in regulating the immune response, and therefore play an important role in the defense against infection and control of autoimmune diseases. However, a therapeutic role of regulatory T cells in an established disease has not been fully established. In this study, we provide direct evidence that CD4(+)CD25(+) regulatory T cells can cure an established, severe, and progressive colitis. SCID mice developed severe colitis when adoptively transferred with naive CD4(+)CD25(-) T cells and infected with the protozoan parasite Leishmania major. The disease development can be completely halted and symptoms reversed, with a healthy outcome, by transferring freshly isolated or activated CD4(+)CD25(+) T cells from syngeneic donors. The therapeutic effect of the regulatory T cells was completely blocked by treatment of the recipients with anti-IL-10R, anti-CTLA4, or anti-TGF-beta Ab. However, the resurgence of colitis under these treatments was not accompanied by the reactivation of Th1 or Th2 response nor was it correlated to the parasite load. These results therefore demonstrate that CD4(+)CD25(+) T cells are therapeutic and that the effect is mediated by both IL-10/TGF-beta-dependent and independent mechanisms. Furthermore, colitis can manifest independent of Th1 and Th2 responses.
- Published
- 2003
- Full Text
- View/download PDF
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