scholarly journals Retracted: Inhibition of MicroRNA-23b Attenuates Immunosuppression During Late Sepsis Through NIK, TRAF1, and XIAP

2018 ◽  
Vol 218 (2) ◽  
pp. 300-311 ◽  
Author(s):  
Haiju Zhang ◽  
Hui Li ◽  
Aamir Shaikh ◽  
Yi Caudle ◽  
Baozhen Yao ◽  
...  
Keyword(s):  
T Cell ◽  
Cecal Ligation ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Signal Pathway ◽  
Interleukin 4 ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Luciferase Reporter ◽  
Apoptosis Protein ◽  
Cecal Ligation Puncture

AbstractBackgroundmicroRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis-induced immunosuppression.MethodsMice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)–induced sepsis. Apoptosis in spleens and apoptotic signals were investigated, and survival was monitored. T-cell immunoreactivities were examined during late sepsis. Nuclear factor κB (NF-κB)–inducing kinase (NIK), tumor necrosis factor (TNF)–receptor associated factor 1 (TRAF1), and X-linked inhibitor of apoptosis protein (XIAP), the putative targets of miR-23b, were identified by a dual-luciferase reporter assay.ResultsmiR-23b expression is upregulated and sustained during sepsis. The activation of the TLR4/TLR9/p38 MAPK/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased the number of spleen cells positive by terminal deoxynucleotidyl transferase dUTP nick-end labeling and improved survival. miR-23b inhibitor restored the immunoreactivity by alleviating the development of T-cell exhaustion and producing smaller amounts of immunosuppressive interleukin 10 and interleukin 4 during late sepsis. We demonstrated that miR-23b mediated immunosuppression during late sepsis by inhibiting the noncanonical NF-κB signal and promoting the proapoptotic signal pathway by targeting NIK, TRAF1, and XIAP.ConclusionsInhibition of miR-23b reduces late-sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression.

scholarly journals Role of CD28 in fatal autoimmune disorder in scurfy mice

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1199-1206 ◽  
Author(s):  
Nagendra Singh ◽  
Phillip R. Chandler ◽  
Yoichi Seki ◽  
Babak Baban ◽  
Mayuko Takezaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Early Death ◽  
Interleukin 10 ◽  
Lymphoproliferative Disease ◽  
Interleukin 4 ◽  
Loss Of Function ◽  
Foxp3 Gene

Abstract Scurfy mice develop CD4 T-cell–mediated lymphoproliferative disease leading to death within 4 weeks of age. The scurfy mutation causes loss of function of the foxp3 gene (foxp3sf), which is essential for development and maintenance of naturally occurring regulatory CD4 T cells (nTregs). In humans, mutations of the foxp3 gene cause immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX). In most patients with IPEX and also in scurfy mice, T cells show hyperreactivity and levels of Th1- and Th2-associated cytokines are substantially elevated. We report that removal of CD28 expression rescued scurfy mice from early death. Longer-term surviving CD28-deficient scurfy mice still had lymphoproliferative disorder, but their CD4 T cells showed decreased interferon-γ and no sign of interleukin-4 or interleukin-10 hyperproduction. Furthermore, injection of CTLA4-Ig to block CD28-B7 interactions substantially improved the survival of scurfy mice by blocking effector T-cell differentiation. These data support the hypothesis that CD28-B7 interactions play a critical role in the etiology of lethal autoimmune disease in scurfy mice by stimulating the differentiation of antigen-activated naive T cells into effector T cells.

Ovarian Cancer Cells Induce Peripheral Mature Dendritic Cells to Differentiate Into Macrophagelike Cells In Vitro

2009 ◽  
Vol 19 (9) ◽  
pp. 1487-1493 ◽  
Author(s):  
Fangxue Chen ◽  
Meng Hou ◽  
Feng Ye ◽  
Weiguo Lv ◽  
Xing Xie
Keyword(s):  
Ovarian Cancer ◽  
Dendritic Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Fluorescein Isothiocyanate ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Ovarian Cancer Cells ◽  
Macrophage Colony

Aims:Precursors of dendritic cells (DCs) are able to differentiate into macrophages induced by some tumor-associated molecules; however, whether peripheral mature DCs could differentiate into macrophages remains unknown. This study was designed to find out whether ovarian cancer cells could induce peripheral mature DCs to differentiate into macrophages.Main Methods:Mature DCs were cultured from monocytes with granulocyte-macrophage colony-stimulating factor and interleukin 4 (IL-4) for 6 days and lipopolysaccharide for another 24 hours and then were cocultured for 48 hours with ovarian cancer ascites or cell-free supernatants of SKOV3 and CAOV3 cell lines. In some experiments, mature DCs were cultured in the absence or presence of IL-10 or leukemia inhibitory factor (LIF) for the same time. In neutralization experiments, neutralizing monoclonal antibodies to IL-10 or LIF were added to the cultures. Cell phenotypes and phagocytosis were analyzed using flow cytometry; allogeneic T-cell proliferation assay was used to examine stimulatory activity of cells.Results and Conclusions:Mature DCs cocultured with ovarian cancer ascites or supernatants of SKOV3 and CAOV3 differentiated into a group of macrophagelike cells that exhibited increased expression of surface marker CD14+CD1a−, decreased expression of CD83, poorer T-cell costimulatory properties, and greater endocytosis of fluorescein isothiocyanate-dextran in vitro. Interleukin 10 but not LIF mediated this differentiation pathway.

scholarly journals miR-25 inhibits sepsis-induced cardiomyocyte apoptosis by targetting PTEN

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Yulong Yao ◽  
Fangyuan Sun ◽  
Ming Lei
Keyword(s):  
Cecal Ligation ◽  
Inhibitory Effect ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Assay ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Luciferase Reporter ◽  
Tensin Homolog ◽  
Tnf Α ◽  
Factor Α

To investigate the regulatory mechanism of miR-25 in sepsis-induced cardiomyocyte apoptosis. Rats models of sepsis were established by cecal ligation and puncture (CLP). Lipopolysaccharide (LPS)-induced cardiomyocyte was used as an in vitro model of sepsis. The expressions of miR-25, tensin homolog deleted on chromosome 10 (PTEN), Toll-like receptors 4 (TLR4), and p-p65 were analyzed by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated d-UTP nick end labeling (TUNEL) assay. The relationship between miR-25 and PTEN was measured by luciferase reporter assays. MiR-25 expression in serum of CLP rats and LPS-induced cardiomyocyte was decreased, while the contents of TNF-α and IL-6 were increased. Moreover, the expressions of PTEN, TLR4, and p-p65 in LPS-induced cardiomyocyte were significantly increased. Overexpression of miR-25 increased the survival rate of rats, inhibited LPS-increased cardiomyocyte apoptosis, reversed the increased expression of PTEN, TLR4, p-p65, TNF-α, and IL-6 induced by LPS. The luciferase assay demonstrated that PTEN was a target of miR-25. Additionally, pcDNA-PTEN reversed the inhibitory effect of miR-25 mimic on cardiomyocyte apoptosis, while TAK-242 (TLR-4 inhibitor) countered this effect. miR-25 reduced LPS-induced cardiomyocyte apoptosis by down-regulating PTEN/TLR4/NF-κB axis.

scholarly journals Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts

Blood ◽  
1995 ◽  
Vol 85 (3) ◽  
pp. 842-851 ◽  
Author(s):  
BR Blazar ◽  
PA Taylor ◽  
S Smith ◽  
DA Vallera
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Graft Rejection ◽  
Acute Gvhd ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Clinical Appearance ◽  
Neutralizing Monoclonal Antibody

Studies in mice and humans have indicated that the predominance of interleukin-4 (IL-4)- and IL-10-producing T-helper type 2 (Th2) cells may serve to downregulate acute graft-versus-host disease (GVHD) reactions, whereas IL-2-producing Th1 cells have been implicated in facilitating acute GVHD. We explored the possibility that the in vivo infusion of IL-10 would inhibit acute GVHD induced by fully allogeneic donor grafts. Unexpectedly, IL-10 infusions resulted in a dose- dependent increase in GVHD-induced mortality. The acceleration of lethal GVHD by IL-10 occurred in irradiated recipients of T-cell- depleted bone marrow (BM) plus 5, 15, or 25 x 10(6) splenocytes but did not influence the post-BM transplantation (post-BMT) survival rate of recipients of BM without splenocytes, suggesting that the IL-10 effects were not due to toxicity. Antimurine IL-10-neutralizing monoclonal antibody injections, administered to diminish endogenous IL-10, reduced GVHD-associated mortality and improved the clinical appearance of the recipients. For BM graft rejection studies, IL-10 was infused into sublethally irradiated recipients of anti-Thy 1.2 + C′ T-cell-depleted, fully allogeneic BM grafts. In a short-term (day 7) in vivo assay, IL- 10 infusions significantly inhibited allogeneic (but not syngeneic) BM proliferation in vivo, indicative of increased graft rejection. In long- term chimerism experiments, IL-10 infusions caused a significant increase in early post-BMT mortality caused by a profound anemia typically associated with graft rejection and aplasia. A slightly higher irradiation dose (650 cGy v 600 cGy) eliminated the anemia but did not reverse the graft rejection process associated with IL-10 administration. We conclude that the in vivo infusion of exogenous IL- 10 in recipients of fully allogeneic donor grafts results in accelerated GVHD and graft rejection in the strain combinations tested to date.

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