Stem Cell Research Laboratory of Jiangsu Province

Laboratory of, China

Stem Cell Research Laboratory of Jiangsu Province

Laboratory of, China
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Sun J.,Suzhou Health Technology College | Fu F.,Soochow University of China | Fu F.,First Affiliated Hospital | Gu W.,Soochow University of China | And 12 more authors.
PLoS ONE | Year: 2011

B7-H3, a recently identified B7 family member, has different isoforms in human and mouse. Mouse B7-H3 gene has only one isoform (2IgB7-H3) with two Ig-like domains, whereas human B7-H3 has two isoforms (2IgB7-H3 and 4IgB7-H3). In this study a systematic genomic survey across various species from teleost fishes to mammals revealed that 4IgB7-H3 isoform also appeared in pigs, guinea pigs, cows, dogs, African elephants, pandas, megabats and higher primate animals, which resulted from tandem exon duplication. Further sequence analysis indicated that this duplication generated a new conserved region in the first IgC domain, which might disable 4IgB7-H3 from releasing soluble form, while 2IgB7-H3 presented both membrane and soluble forms. Through three-dimensional (3D) structure modeling and fusion-protein binding assays, we discovered that the duplicated isoform had a different structure and might bind to another potential receptor on activated T cells. In T cell proliferation assay, human 2IgB7-H3 (h2IgB7-H3) and mouse B7-H3 (mB7-H3) both increased T cell proliferation and IL-2, IFN-γ production, whereas human 4IgB7-H3 (h4IgB7-H3) reduced cytokine production and T cell proliferation compared to control. Furthermore, both h2IgB7-H3 and mB7-H3 upregulated the function of lipopolysacharide (LPS)-activated monocyte in vitro. Taken together, our data implied that during the evolution of vertebrates, B7-H3 exon duplication contributed to the generation of a new 4IgB7-H3 isoform in many mammalian species, which have carried out distinct functions in the immune responses. © 2011 Sun et al.

Chen Q.,Soochow University of China | Xia X.,Soochow University of China | Xia X.,Nantong Tumor Hospital | Wu S.,Soochow University of China | And 12 more authors.
Cell Biochemistry and Function | Year: 2014

Enterocytes die during high-dose radiation exposure in radiation accidents. The modality of cell death has a profound effect on the therapeutic response. The ilea from mice with 15Gy total body irradiation (TBI) were drawn, morphological features observed by hematoxylin and eosin staining and transmission electron micrographs. The biochemical features of mouse ileum presented with the structure were cleaved Caspase-3 (apoptosis marker), Light Chain 3 (LC3)-I's conversion to LC3-II (autophagy marker) and high mobility group box chromosomal protein 1's secretion (necrosis marker). Then, the autophagy inhibitor (3-methyladenine), caspase inhibitor (Z-VAD-FMK) or necrosis inhibitor (necrostatin) was used to prevent death. Apoptosis, autophagy and necrosis were all appeared in the ileum, but necrosis had the biggest size; the use of 3-methyladenine and Z-VAD-FMK prolong one day's life of the mice after 15Gy TBI, necrostatin significantly extended the lifespan of 15Gy irradiated mice (p<0.05). The results suggest that the death of enterocytes could not be classified into one type of cell death but rather as 'mixed death.' © 2014 John Wiley & Sons, Ltd.

Wang Q.,Soochow University of China | Shi B.-M.,Soochow University of China | Xie F.,Soochow University of China | Fu Z.-Y.,Soochow University of China | And 7 more authors.
Molecular and Cellular Endocrinology | Year: 2016

OX40/OX40L pathway plays a very important role in the antigen priming T cells and effector T cells. In the present study, we aimed to examine the involvement of OX40/OX40L pathway in the activation of autoreactive T cells in patients with Grave's disease (GD). We found that OX40 and OX40L were constitutively coexpressed on peripheral CD4+ T cells from GD patients using flow cytometry analysis. The levels of OX40 and OX40L coexpression on CD4+ T cells were shown to be correlated with TRAbs. Cell proliferation assay showed that blocking OX40/OX40L signal inhibited T cell proliferation and survival, which suggested that OX40/OX40L could enhance CD4+ T cell proliferation and maintain their long-term survival in GD by self-enhancing loop of T cell activation independent of APCs. Confocal microscopy and coimmunoprecipitation analysis further revealed that OX40 and OX40L formed a functional complex, which may facilitate signal transduction from OX40L to OX40 and contribute to the pathogenesis of GD. © 2016 Elsevier Ireland Ltd.

Chen Y.,Soochow University of China | Chen Y.,Key Laboratory of Infection and Immunity | Wang Q.,Soochow University of China | Wang Q.,Stem Cell Research Laboratory of Jiangsu Province | And 7 more authors.
Cytokine | Year: 2011

PD-L1 (CD274) is a critical membrane-bound costimulatory molecule that inhibits immune responses through its receptor, PD-1. Previous data have showed that this molecule is associated with autoimmune diseases, chronic viral infections and tumor immune escape. However, the existence and role of soluble form of human PD-L1 (sPD-L1) remain unknown. We show here that a novel enzyme-linked immunosorbent assay (ELISA) was developed to detect the sPD-L1 protein. Many culture supernatants of the PD-L1 + cell lines contain high levels of this factor. Interestingly, the sPD-L1 is detectable in human serum and the concentration increases in an age-dependent manner. Human sPD-L1 has a unique protein form in the serum and the matrix metalloproteinase inhibitor (MMPI) could suppress sPD-L1 production. Moreover, the sPD-L1 could specially bind to PD-1. Together, these data demonstrate that the existence of circulating sPD-L1 in human serum might play an important role in immunoregulation. © 2011 Elsevier Ltd.

Liu W.,Soochow University of China | Chen Q.,Soochow University of China | Wu S.,Soochow University of China | Xia X.,Soochow University of China | And 6 more authors.
Journal of Radiation Research | Year: 2015

The identification of an agent effective for the treatment of intestinal and bone marrow injury following radiation exposure remains a major issue in radiological medicine. In this study, we evaluated the therapeutic impact of single agent or combination treatments with 2-(3-aminopropylamino) ethylsulphanyl phosphonic acid (WR- 2721) and peptidoglycan (PGN, a toll-like receptor 2 (TLR-2) agonist) on radiation-induced injury of the intestine and bone marrow in lethally irradiated male C57BL/6 mice. A dose of 3 mg of WR-2721 per mouse (167 mg/kg, intraperitoneally) was given 30 min before irradiation, and 30 μg of PGN per mouse (1.7 mg/kg) was injected intraperitoneally 24 h after 10 Gy irradiation. Bone marrow cluster of differentiation (CD)45+ and CD34+ markers of multiple haematopoietic lineages, number of granulocyte-erythroid-macrophage-megakaryocyte (GEMM) progenitor colonies, bone marrow histopathology, leucine-rich repeat-containing G-proteincoupled receptor 5 (Lgr5) expression in the intestines, xylose absorption and intestinal histopathology were all assessed at various time-points after irradiation. Furthermore, nuclear factor kappa B (NF-κB) p65 protein in the ileum was stained by immunofluorescent labelling. PGN-treated irradiated mice showed an increase in CD45+CD34+ cells compared with untreated mice 1.25 days after 10 Gy ionizing radiation (IR) (P < 0.05). Furthermore, combined PGN and WR-2721 treatment had an obviously synergistic radio-protective effect in nucleated cells in the bone marrow, including GEMM progenitors and CD45+CD34+ cells 4 days after 10 Gy IR. Single agent PGN or WR-2721 treatment after 10 Gy IR clearly increased Lgr5-positive pit cells (P < 0.05) and xylose absorption (P < 0.05). However only PGN and WR-2721 combination treatment markedly increased villus height (P < 0.05), number of crypts (P < 0.05) and whole-body weights after 10 Gy whole-body irradiation (WBI). The NF-κB p65 subunit was translocated to the nucleus, and phosphate-IκBα (Ser32/Ser36) was detected after stimulation with either PGN or WR-2721, which indicates that these two agents act synergistically through the activation of the NF-κB pathway. Administration of PGN in combination with WR-2721 was demonstrated to have a synergistic effect on the increase in haematopoietic cells and intestinal reconstitution, as well as improved survival in lethally irradiated mice, but resulted in some degree of an immune disorder. © The Author 2015.

PubMed | Stem Cell Research Laboratory of Jiangsu Province and Soochow University of China
Type: Journal Article | Journal: Oncotarget | Year: 2016

Immediate medical intervention is required after pelvic tumor radiotherapy to protect the radiosensitive intestine and also to mitigate tumor growth. Toll-like receptors (TLRs) have been shown to promote tissue repair processes. Here, we analyzed the effect observed upon combining the TLR2 agonist, peptidoglycan (PGN), with radiation therapy on tumors as well as intestinal tissue, both in vitro and in vivo. In contrast to radiotherapy alone, PGN when combined with ionizing radiation (IR) elicited enhanced antitumor effects and also reduced the IR-induced intestinal damage. Mechanistic studies showed that PGN first induced an IL13 response in the irradiated intestine, but was decreased in tumor cell models screened by Th1/Th2 FlowCytomix assay and validated by the application of IL13 and anti-IL13 neutralizing antibodies. Next, PGN stimulated Akt3, but not Akt1/2, as was verified by AKT1/2/3 plasmid transfection assay and in AKT1/2/3 knockout mice in vivo. Akt3 expression was inhibited in 20 g/mL PGN-treated tumor cells and in 1.5 mg/kg PGN-treated mouse tumor models. However, Akt3 was raised via IL13 in the irradiated intestine and human intestinal cell line after the same treatment. Finally, PGN activated mTOR via IL13/AKT3 in the intestine and restored intestinal structure and function. As an adjuvant to radiotherapy, PGN inhibited tumorigenesis by suppression of mTOR activity. To summarize, the IL13/AKT3/mTOR pathway was lessened in PGN-treated irradiated tumors but was raised in the normal intestine tissue. This distinct effect of PGN on normal and tumor tissues during pelvic radiotherapy suggests that PGN may be a promising adjuvant therapy to radiation.

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