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Zhenya Hong,
Min Xiao,
Yang Yang,
Zhiqiang Han,
Yang Cao,
Chunrui Li,
Ying Wu, Quan Gong,
Xiaoxi Zhou,
Danmei Xu,
Li Meng,
Ding Ma,
Jianfeng Zhou
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ABSTRACT: Although dramatic clinical success has been achieved in acute promyelocytic leukemia (APL), the success of differentiating agents has not been reproduced in non-APL leukemia. A key barrier to the clinical success of arsenic is that it is not potent enough to achieve a clinical benefit at physiologically tolerable concentrations by targeting the leukemia cell differentiation pathway alone. We explored a novel combination approach to enhance the eradication of leukemia stem cells (LSCs) by arsenic in non-APL leukemia. In the present study, phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin (mTOR) phosphorylation was strengthened after As(2)S(2) exposure in leukemia cell lines and stem/progenitor cells, but not in cord blood mononuclear cells (CBMCs). propidium iodide-103, the dual PI3K/mTOR inhibitor, effectively inhibited the transient activation of the PI3K/AKT/mTOR pathway by As(2)S(2). The synergistic killing and differentiation induction effects on non-APL leukemia cells were examined both in vitro and in vivo. Eradication of non-APL LSCs was determined using the nonobese diabetic/severe combined immunodeficiency mouse model. We found that a combined As(2)S(2)/PI-103 treatment synergized strongly to kill non-APL leukemia cells and promote their differentiation in vitro. Furthermore, the combined As(2)S(2)/PI-103 treatment effectively reduced leukemia cell repopulation and eradicated non-APL LSCs partially via induction of differentiation while sparing normal hematopoietic stem cells. Taken together, these findings suggest that induction of the PI3K/AKT/mTOR pathway could provide a protective response to offset the antitumor efficacy of As(2)S(2). Targeting the PI3K/AKT/mTOR pathway in combination with As(2)S(2) could be exploited as a novel strategy to enhance the differentiation and killing of non-APL LSCs.
Carcinogenesis 07/2011; 32(10):1550-8. · 5.70 Impact Factor
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ABSTRACT: This study was aimed to investigate the expression of CD96 on bone marrow mononuclear cells (BMMNC) from 91 patients with acute leukemia, and the results were analyzed with clinical pathological data. Flow cytometry was used to detect CD96 molecule on the bone marrow mononuclear cell surface of 91 newly diagnosed patients with acute leukemia, and 15 healthy adults were served as normal controls. The results showed that the average rate of CD96(+) expression on BMMNC (CD45(+) CD34(+) CD19(+)) of 21 patients with B-ALL was (17.41 ± 27.97)%, the average rate of CD96(+) expression on stem cells (CD45(+)CD34(+)CD7(+)) of 11 patients with T-ALL was (46.98 ± 45.55)%, the average rate of CD96(+) expression on BMMNC (CD45(+)CD34(+)CD38(-)) of 59 patients with AML was (16.69 ± 25.08)%, while the average rate of CD96(+) on BMMNC of healthy adult controls was (0.52 ± 1.84)%, there was significant difference in average rate of CD96(+) expression between above-mentioned patients and healthy adult controls (p < 0.05). Otherwise the average rate of CD96(+) on BMMNC after treatment showed no statistical difference between patient group with CR (1.68 ± 2.31) and healthy controls, but demonstrated statistical difference between patients without CR and healthy controls (p > 0.05). The leukocyte count, hemoglobin level and platelet count in CD96(+) group had no obvious difference from CD96(-) ones (p > 0.05). No change found in the field of molecular biology and cytogenetic between these 2 groups. It is concluded that CD96 expression is different in different types of leukemia. The positive expression of CD96 on bone marrow hematopoietic stem cells in patients with acute leukemia may be associated with primary drug resistance, relapse and progression. The CD96 on BMMNC of acute leukemias can be a helpful prognostic indicator in treatment response assessment.
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 06/2011; 19(3):585-8.
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Junhua Li, Quan Gong,
Shan Zhong,
Lu Wang,
Hui Guo,
Ying Xiang,
Tomas E Ichim,
Cong-Yi Wang,
Shi Chen,
Feili Gong,
Gang Chen
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ABSTRACT: Graft quality, comprised of ischaemia-reperfusion injury (IRI) and surgical manipulation, is one of the major factors influencing transplant rejection. High-mobility group box 1 (HMGB1), a known activator of innate immunity, has been associated with tissue-generated immunological 'danger' signals; however, its role in renal IRI is not clear.
Renal IRI was induced by clamping the left renal pedicle for 60 min in uninephrectomized BALB/c mice. Rabbit anti-mouse HMGB1 antibody was given intraperitoneally 24 h and 30 min before renal ischaemia. Renal HMGB1 expression was assessed by immunohistochemistry and western blot. The therapeutic effect of HMGB1 neutralizing antibody on IRI was evaluated in terms of renal function, histological and immunopathologic examination and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labelling assays.
Ischaemia alone was associated with release of HMGB1, which after reperfusion appeared to induce localization of HMGB1 to renal tubules, peritubular capillaries and glomeruli where the renal cells might be more susceptible to ischaemic insult. Administration of blocking antibody to HMGB1 was associated with reduction in tubular apoptosis and inflammation (TNF-α expression) in situ and in vivo with preservation of renal function.
These data suggest that released HMGB1 by ischaemic renal parenchyma cells may act as an essential early mediator in delayed inflammatory response during IRI, and targeting HMGB1 may represent a potential approach in the prevention of clinical IRI associated with kidney transplantation.
Nephrology Dialysis Transplantation 02/2011; 26(2):469-78. · 3.40 Impact Factor
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ABSTRACT: Previously, we reported that extracellular high-mobility group box 1 (HMGB1) functions as an innate alarmin implicated in cardiac allograft acute rejection. We now present evidence suggesting that HMGB1 is pivotal in inducing interleukin-17 (IL-17)-producing alloreactive T cells by stimulating dendritic cells secretion of IL-6. Those IL-17(+) T cells are likely to be the major effector cells responsible for the early stage of cardiac allograft rejection through mediating an influx of neutrophils into allografts, and therefore, blockade of IL-17A significantly prolonged murine cardiac allograft survival. In contrast to the classical model for a dominant role of IFN-γ(+)-Th1 cells have in acute allograft rejection, our data suggest that IFN-γ(+)-Th1 cells are responsible for the late stage of graft destruction by inducing monocyte infiltration when IL-17(+) T-cell response recedes. Blockade of HMGB1 significantly decreased splenic alloreactive Th17 cells and IFN-γ-producing CD8(+) T cells in the recipients, leading to less infiltration of neutrophils along with lower IL-6 and IL-17 expression levels in the grafts as well as prolongation of cardiac allograft survival. Together, these data support a novel model in which HMGB1 induces IL-17-producing alloreactive T cells to mediate early stage of allograft rejection, whereas IFN-γ-producing alloreactive Th1 cells provoke graft destruction after Th17 response recedes.
Laboratory Investigation 01/2011; 91(1):43-53. · 3.64 Impact Factor
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Quan Gong,
Hui Zhang,
Jun-hua Li,
Li-hua Duan,
Shan Zhong,
Xiao-ling Kong,
Fang Zheng,
Zheng Tan,
Ping Xiong,
Gang Chen,
Min Fang,
Fei-li Gong
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ABSTRACT: High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as an early endogenous alarmin of inflammation following injury and as a late mediator of lethality in sepsis. Although HMGB1 has been implicated in acute lung injury, rheumatoid arthritis, and allograft rejection, its role in T-cell mediated hepatitis remains obscure. Here, we investigated the role and the underlying mechanisms of HMGB1 in concanavalin A (Con A) induced hepatic injury. We demonstrate that high levels of HMGB1 were detected in the necrotic area and in the cytoplasm of hepatocytes after Con A treatment. Administration of exogenous recombinant HMGB1 enhanced Con A-induced hepatitis, while blockade of HMGB1 protected animals from T cell-mediated hepatitis as evidenced by decreased serum transaminase, associated with reduced hepatic necrosis and mortality. Blockade of HMGB1 by a neutralizing antibody inhibited proinflammatory cytokine production, NFκB activity, and the late stage of T/NKT cell activation. These finding thus suggest a pivotal factor of HMGB1 in Con A-induced hepatitis. Blockage of extracellular HMGB1 may represent a novel therapeutic strategy to prevent hepatic injury in T cell-mediated hepatitis.
Journal of Molecular Medicine 12/2010; 88(12):1289-98. · 4.67 Impact Factor
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ABSTRACT: This study was designed to determine the impact of chrysoeriol on proliferation and cell cycle progression in the human multiple myeloma cell lines RPMI 8226 and KM3, and its related molecular mechanisms. Chryseoriol was identified by using the phosphorylated AKT-specific cytoblot high throughput assay. CCK-8 assay was employed to examine the growth inhibition rate and IC(50) (48 h) in peripheral blood mononuclear cells (PBMNCs), RPMI 8226 and KM3 cells treated with chrysoeriol at various concentrations. Cells were labeled with 5-6-carboxyfluorescein diacetate succinimidyl ester (CFSE), and the proliferation dynamics was detected by flow cytometry and analyzed with ModFit software. The cell cycles of RPMI 8226 and KM3 cells were measured by flow cytometry when the IC(50) concentration of chrysoeriol was adopted. The alterations in cell-cycle related proteins (Cyclin B1, Cyclin D1, p21) and proteins in PI3K-AKT-mTOR pathway were determined by Western blot analysis. The results showed the proliferation of multiple myeloma cells was significantly inhibited by chrysoeriol, resulting in cell cycle arrest in G(2)/M phase. Chrysoeriol could significantly reduce the expression of p-AKT (s473) and p-4eBP1 (t37/46) protein, meanwhile enhanced Cyclin B1 and p21 protein expression. Similar effects were not observed in PBMNCs from normal donors. It was concluded that chrysoeriol was a selective PI3K-AKT-mTOR pathway inhibitor. It restrained the proliferation of human multiple myeloma cells, but didn't affect proliferation of PBMNCs from normal donors. It might exhibit the cell cycle regulatory effect via the inhibition of PI3K-AKT-mTOR signal pathway.
Journal of Huazhong University of Science and Technology 12/2010; 30(6):734-40. · 0.38 Impact Factor
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ABSTRACT: Although studies have demonstrated that heme oxygenase-1 (HO-1) prevents leukocyte infiltration and organ damage following LPS challenge, the mechanisms involved in this protection are incompletely understood. Macrophage migration inhibitory factor (MIF) is thought to play a pivotal role in modulation of inflammatory and immune response through upregulation of TLR4 expression. Activation of TLR4 results in the production of proinflammatory mediators including MIF, which induce neutrophils recruitment and subsequent tissue insults. We hypothesized that HO-1 mediates its salutary effects in lipopolysaccharide (LPS)-induced inflammatory lung injury via downregulation of MIF through modulation of TLR4-induced proinflammatory mediator production. Compared with wild-type cells, MIF-knockdown macrophages in vitro are hyporesponsive to LPS stimulation, as shown by a profound reduction in TLR4 expression and TNF-alpha production. In the murine model of LPS-induced acute lung injury, administration of CoPP, a potent HO-1 inducer, leaded to a significant reduction in LPS-induced pulmonary edema, leucocytes influx, myeloperoxidase activity as well as histopathologic insults. Most strikingly, pretreatment with CoPP markedly decreased the expression of TLR4 and MIF in lung tissues in response to LPS challenge. These findings herein suggest that the cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response.
Molecular Immunology 09/2010; 47(15):2443-9. · 2.90 Impact Factor
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ABSTRACT: In Th (T helper) 1/Th2 balance in response to signals given during donor antigen presentation, induction of allograft prolongation is more often related to Th2-type than with Th1-type immunity. Here, we examined the effect of interleukin (IL)-33, a novel member of the IL-1 family, on cardiac allograft survival in mice.
Mice heterotopic cardiac transplants were performed with sequential recipient sacrifice at anticipated time points to examine the immunoregulatory action of IL-33 in recipient mice.
In vitro Th1-polarized CD4 T cells did not express ST2L; however, most CD4 T cells became ST2L on repeated stimulation under Th2-polarizing conditions. Similarly, we found that IL-33 was able to enhance the expression of Th2-associated cytokines (IL-5 and IL-13) but not interferon (IFN)-gamma. Treatment of recipient mice with IL-33 results in the improvement of allograft survival (more than 20 days) when compared with phosphate-buffered saline- or glutathione S-transferase-treated groups (all less than 9 days). Intracellular cytokine staining in CD4 splenocytes confirmed an increase in the percentage of IL-4 cells and a decrease in the percentage of IFN-gamma cells in IL-33 treated mice. In addition, IL-33 significantly enhanced the gene expression of Th2-type cytokines IL-4 and IL-5 but suppressed the Th1-type cytokine IFN-gamma mRNA levels in both allograft and recipient spleen.
These data demonstrate that IL-33 serves as a potent inducer of Th2 immune response and can markedly contribute to the prolongation of cardiac allograft survival.
Transplantation 03/2010; 89(10):1189-97. · 4.00 Impact Factor
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ABSTRACT: It has been reported that splenic stromal cells (SSCs) are capable of directly supporting the development of CD11c(lo)CD45RB(+ )IL-10-producing dendritic cells (DCs) from lineage-negative c-kit(+) progenitor cells in the absence of exogenous cytokines. In vitro, DCs that differentiate on stromal cells suppress mixed leukocyte reaction responses and induce primary alloreactive CD4(+) T cells to differentiate into IL-10-producing Tr1 cells. However, the precise mechanisms by which these SSCs exert their regulatory functions in vivo remain undefined. Furthermore, their possible contribution to the development of allograft transplantation tolerance has yet to be examined. Here, we have used both murine skin and cardiac allograft transplantation models to explore whether in vivo alloresponses can be regulated by infusion with donor-derived SSCs and to investigate the possible mechanisms by which SSCs exert regulatory effects to prevent allograft rejection. We show that intravenous SSC infusion prolonged murine skin allograft survival. The prolonged graft survival is associated with augmentation of the generation of regulatory DC subsets and CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), as well as upregulation of the production of suppressive cytokines IL-10 and transforming growth factor (TGF)-β. Moreover, we found that indoleamine 2,3-dioxygenase and SSC-derived regulatory DCs contribute to allograft protection by infusion of donor-specific SSCs. Our data suggest that donor-derived SSCs could be used as a therapeutic target to promote transplantation tolerance.
Cellular & molecular immunology 01/2010; 8(1):31-40. · 2.99 Impact Factor
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Hui Zhang, Quan Gong,
Jun-hua Li,
Xiao-ling Kong,
Li Tian,
Li-hua Duan,
Jing Tong,
Fei-fei Song,
Min Fang,
Fang Zheng,
Ping Xiong,
Zheng Tan,
Fei-li Gong
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ABSTRACT: T cell-mediated hepatic damage plays a key role in the pathogenesis of liver diseases such as autoimmune hepatitis, viral hepatitis and acute liver failure. CpG-containing oligodeoxynucleotides (CpG ODN), a ligand for toll-like receptor (TLR) 9, is widely used as an immunological adjuvant. In the present study, we investigated the effect of CpG ODN on T cell-mediated liver injury in a murine model of concanavalin A (Con A)-induced hepatitis. We found that the aminotransferase level was significantly decreased in CpG ODN pretreated mice and the survival of the mice was markedly prolonged. CpG ODN pretreatment inhibited NF-kappaB DNA binding activity. As a result, the systemic/liver levels of TNF-alpha and IFN-gamma were significantly suppressed. Furthermore, the activation of inflammatory cells was diminished by CpG ODN pretreatment. These results suggest that CpG ODN pretreatment protects the mice from Con A-induced liver injury via inhibiting hepatocyte apoptosis, inflammation and activation of lymphocytes.
International immunopharmacology 10/2009; 10(1):79-85. · 2.21 Impact Factor
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Chun-Lei Yuan,
Jun-Fa Xu,
Jing Tong,
Heng Yang,
Feng-Rong He, Quan Gong,
Ping Xiong,
Lihua Duan,
Min Fang,
Zheng Tan,
Yong Xu,
Yi-Fa Chen,
Fang Zheng,
Fei-Li Gong
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ABSTRACT: B7-H4, a recently discovered member of B7 family, can negatively regulate T cell responses. However, it is not clear whether B7-H4 negatively function in cell transplantation. In this study we investigated the immunosuppressive effect of B7-H4 on beta-cell transplantation. An insulinoma cell line, NIT-1, transfected with B7-H4 (B7-H4-NIT) was established, and transplanted to diabetic C57BL/6 mice by intraperitoneal injection. Proliferation assay of splenocytes in vitro showed that B7-H4-NIT suppressed alloreactive T cell activation. The proportion of IFN-gamma-producing cells in recipient spleen was significantly reduced and the number of Treg cells was upregulated in B7-H4-NIT group compared to the control, EGFP-NIT. The expression of mRNA coding IFN-gamma was lower but that of IL-4 was higher in B7-H4-NIT transplanted recipients than in the control animals. The results of ELISA also revealed the same trends. Diabetic mice reached normalglycemic quickly and gained weight after transplantation of B7-H4-NIT. More importantly, the survival time for recipients transplanted with B7-H4-NIT cells was significantly longer than that with EGFP-NIT cells. These results indicate that B7-H4 transfection prolongs beta-cell graft survival.
Transplant Immunology 05/2009; 21(3):143-9. · 1.46 Impact Factor
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ABSTRACT: Fructose-1,6-diphosphate (FDP), a high-energy glycolytic pathway intermediate, is reported to have a salutary effect in endotoxic shock and sepsis, but its underlying mechanism of action in inflammation is incompletely understood. In this study, our aim was to examine the function of FDP on acute lung injury (ALI) induced by lipopolysaccharide (LPS). We found that in vitro pretreatment with FDP remarkably repressed the production of TNF-alpha and IL-6 in murine alveolar macrophages MH-S exposed to LPS. In the mouse model of LPS-induced inflammatory lung injury, intravenous precondition of a single 400 mg/kg dose of FDP resulted in a significant reduction in LPS-mediated extravasation of Evans blue dye albumin, bronchoalveolar lavage leucocyte content, and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Furthermore, histopathologic examination indicated that alveolitis with inflammatory cells infiltration and alveolar hemorrhage in the alveolar space was less severe in the FDP-treated mice than in the mice treated by LPS alone at 24 h. Additionally, pretreatment with FDP markedly decreased the transcription of TNF-alpha, IL-6 and inducible NO synthase (iNOS), and suppressed the nuclear translocation of NF-kappaB in lung tissues in response to LPS challenge. These results thus suggested that FDP plays an anti-inflammatory role in LPS-mediated acute lung injury, possibly through abrogation of NF-kappaB activation.
International Immunopharmacology 10/2008; 8(13-14):1842-7. · 2.38 Impact Factor
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Quan Gong,
Hui Yin,
Min Fang,
Ying Xiang,
Chun-Lei Yuan,
Guo-Ying Zheng,
Heng Yang,
Ping Xiong,
Gang Chen,
Fei-Li Gong,
Fang Zheng
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ABSTRACT: The present study was designed to investigate whether administration of CoPPIX, an HO-1 inducer, could significantly inhibit TNF-alpha and Hmgb1 expression and thus attenuate the acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Acute lung injury was induced successfully by intratracheal administration of LPS (0.5 mg/kg) in male BALB/c mice. CoPPIX or ZnPPIX (an HO-1 inhibitor) was administered to mice 24 h prior to LPS exposure. It was found that CoPPIX (5, 10 mg/kg, i.p.) caused a significant reduction in the total cells and neutrophils in BALF, a significant reduction in the W/D ratio and EBA leakage at 24 h after LPS challenge. Furthermore, the histopathologic findings indicated that alveolitis with leukocyte infiltration in the alveolar space was less severe in the CoPPIX-treated mice than in the mice treated with LPS alone. In addition, CoPPIX was also believed to have down-regulated the expression of LPS-induced proinflammatory cytokines, including early proinflammatory cytokine TNF-a, and late proinflammatory cytokine Hmgb1. In contrast, no obvious difference was observed between the ZnPPIX group and the LPS group. These findings demonstrate the significant protection of CoPPIX against LPS-induced ALI, and the effect mechanism of CoPPIX was associated with decreasing the expression of TNF-a and Hmgb1.
International Immunopharmacology 07/2008; 8(6):792-8. · 2.38 Impact Factor
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Chun-lei Yuan,
Jun-fa Xu,
Jing Tong,
Heng Yang,
Feng-rong He, Quan Gong,
Ping Xiong,
Lihua Duan,
Min Fang,
Zheng Tan,
Yong Xu,
Yi-fa Chen,
Fang Zheng,
Fei-li Gong
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ABSTRACT: B7-H4, a recently discovered member of B7 family, can negatively regulate T cell responses. However, it is not clear whether B7-H4 negatively function in cell transplantation. In this study we investigated the immunosuppressive effect of B7-H4 on β-cell transplantation. An insulinoma cell line, NIT-1, transfected with B7-H4 (B7-H4-NIT) was established, and transplanted to diabetic C57BL/6 mice by intraperitoneal injection. Proliferation assay of splenocytes in vitro showed that B7-H4-NIT suppressed alloreactive T cell activation. The proportion of IFN-γ-producing cells in recipient spleen was significantly reduced and the number of Treg cells was upregulated in B7-H4-NIT group compared to the control, EGFP-NIT. The expression of mRNA coding IFN-γ was lower but that of IL-4 was higher in B7-H4-NIT transplanted recipients than in the control animals. The results of ELISA also revealed the same trends. Diabetic mice reached normalglycemic quickly and gained weight after transplantation of B7-H4-NIT. More importantly, the survival time for recipients transplanted with B7-H4-NIT cells was significantly longer than that with EGFP-NIT cells. These results indicate that B7-H4 transfection prolongs β-cell graft survival.
Transplant Immunology.
