scholarly journals Butyric Acid-Induced T-Cell Apoptosis Is Mediated by Caspase-8 and -9 Activation in a Fas-Independent Manner

2001 ◽  
Vol 8 (2) ◽  
pp. 325-332 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Kuniyasu Ochiai ◽  
Kazuo Fukushima
Keyword(s):  
T Cells ◽  
T Cell ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Acid Treatment ◽  
Jurkat Cells ◽  
Receptor Interaction ◽  
Caspase 8 ◽  
T Cell Apoptosis ◽  
Induced Apoptosis

ABSTRACT Our previous study demonstrated that butyric acid, an extracellular metabolite of periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat cells. In this study, we examined whether CD95 ligand-receptor interaction is involved in butyric acid-induced T-cell apoptosis. Flow cytometry analysis indicated that expression of Fas in Jurkat and T cells from peripheral blood mononuclear cells was not affected by butyric acid treatment. Furthermore, the expression of Fas and FasL protein in Western blotting was not affected by butyric acid treatment. Coincubation with blocking anti-Fas antibodies prevented Fas-induced apoptosis but not butyric acid-induced apoptosis. Anti-FasL antibodies also did not prevent butyric acid-induced apoptosis at any dose examined. Although cytotoxic anti-Fas antibody affected butyric acid-induced apoptosis, a synergistic effect was not seen. Time-dependent activation of caspase-8 and -9 was recognized in butyric acid- as well as Fas-mediated apoptosis. IETD-CHO and LEHD-CHO, specific inhibitors of caspase-8 and -9, respectively, completely blocked Fas-mediated apoptosis and partially prevented butyric acid-induced apoptosis. These results suggest that the Fas-FasL interaction is not involved in butyric acid-induced apoptosis and that caspase-8 and -9-dependent apoptosis plays an important role in butyric acid-induced apoptosis, as well as Fas-induced apoptosis.

scholarly journals Lipopolysaccharide Stimulates Butyric Acid-Induced Apoptosis in Human Peripheral Blood Mononuclear Cells

1999 ◽  
Vol 67 (1) ◽  
pp. 22-29 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Kazuo Fukushima ◽  
Kuniyasu Ochiai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
T Cell Apoptosis ◽  
Blood Mononuclear Cells ◽  
Induced Apoptosis ◽  
Dose Dependent

ABSTRACT We previously reported that butyric acid, an extracellular metabolite from periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we examined the ability of butyric acid to induce apoptosis in peripheral blood mononuclear cells (PBMC) and the effect of bacterial lipopolysaccharide (LPS) on this apoptosis. Butyric acid significantly inhibited the anti-CD3 monoclonal antibody- and concanavalin A-induced proliferative responses in a dose-dependent fashion. This inhibition of PBMC growth by butyric acid depended on apoptosis in vitro. It was characterized by internucleosomal DNA digestion and revealed by gel electrophoresis followed by a colorimetric DNA fragmentation assay to occur in a concentration-dependent fashion. Butyric acid-induced PBMC apoptosis was accompanied by caspase-3 protease activity but not by caspase-1 protease activity. LPS potentiated butyric acid-induced PBMC apoptosis in a dose-dependent manner. Flow-cytometric analysis revealed that LPS increased the proportion of sub-G1 cells and the number of late-stage apoptotic cells induced by butyric acid. Annexin V binding experiments with fractionated subpopulations of PBMC in flow cytometory revealed that LPS accelerated the butyric acid-induced CD3+-T-cell apoptosis followed by similar levels of both CD4+- and CD8+-T-cell apoptosis. The addition of LPS to PBMC cultures did not cause DNA fragmentation, suggesting that LPS was unable to induce PBMC apoptosis directly. These data suggest that LPS, in combination with butyric acid, potentiates CD3+ PBMC T-cell apoptosis and plays a role in the apoptotic depletion of CD4+ and CD8+ cells.

scholarly journals Human Gingival Fibroblasts Rescue Butyric Acid-Induced T-Cell Apoptosis

2002 ◽  
Vol 70 (5) ◽  
pp. 2361-2367 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Kuniyasu Ochiai ◽  
Naoto Suzuki ◽  
Kichibee Otsuka ◽  
Kazuo Fukushima
Keyword(s):  
T Cells ◽  
T Cell ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Jurkat Cell ◽  
Jurkat Cells ◽  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
T Cell Apoptosis ◽  
Dose Dependent

ABSTRACT We previously demonstrated that butyric acid, an extracellular metabolite from periodontopathic bacteria, induces cytotoxicity and apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we used a cell-to-cell interaction system to examine the contribution of gingival fibroblasts to the regulation of T-cell death induced by butyric acid. Butyric acid slightly suppressed fibroblast viability in a concentration-dependent fashion. However, DNA fragmentation assays indicated that butyric acid did not induce apoptosis for up to 21 h in human gingival fibroblasts (Gin 1, F41-G, and H. pulp cells). The culture supernatants were assayed for interleukin 1α (IL-1α), IL-1β, IL-6, IL-8, IL-11, tumor necrosis factor alpha, and transforming growth factor β, but only the IL-6, IL-8, and IL-11 levels were significantly increased by addition of butyric acid. Butyric acid- or Fas-induced Jurkat-cell apoptosis was attenuated when Jurkat cells were cocultured with either F41-G or Gin 1 cells that had been preincubated for 6 h with butyric acid. IL-8 slightly stimulated butyric acid- or Fas-induced Jurkat-cell apoptosis in a dose-dependent manner, although a low dose of IL-8 had a mildly inhibitory effect on apoptosis. In contrast, IL-6 and IL-11 significantly suppressed butyric acid- or Fas-induced apoptosis in a dose-dependent fashion. Furthermore, the addition of monoclonal antibodies against human IL-6 and IL-11 to cocultures of gingival fibroblasts and Jurkat cells partially eliminated T-cell recovery. These results suggest that the proinflammatory cytokines such as IL-6 and IL-11, produced in fibroblasts stimulated with butyric acid, are involved in the attenuation of T-cell apoptosis by gingival fibroblasts.

scholarly journals Role of Cell-Cell Communication in Inhibiting Butyric Acid-Induced T-Cell Apoptosis

2004 ◽  
Vol 72 (10) ◽  
pp. 5947-5954 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Shintaro Seto ◽  
Kuniyasu Ochiai
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Jurkat Cells ◽  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
T Cell Apoptosis ◽  
T Cell Adhesion

ABSTRACT We have previously demonstrated that human gingival fibroblasts rescue butyric acid-induced T-cell apoptosis via proinflammatory cytokines such as interleukin 6 (IL-6) and IL-11, which are produced by fibroblasts stimulated with butyric acid. In this study, we determined if T-cell adhesion to human gingival fibroblasts influenced the susceptibility of T cells to butyric acid-induced apoptosis. We have shown that the number of Jurkat T cells adherent to gingival fibroblasts (Gin-1 cells) was significantly increased by the addition of butyric acid. All Jurkat cells that adhered to Gin-1 cells remained viable, while the nonadherent Jurkat cells dropped into apoptosis. The increase in T-cell adhesion to fibroblasts was also observed when Jurkat cells, but not Gin-1 cells, were pretreated with butyric acid. The expression levels of CD44, very late antigen 2 (VLA-2) and VLA-5 but not of leukocyte function-associated antigen 1 (LFA-1) and VLA-4 on Jurkat cells were increased following treatment with butyric acid. Furthermore, pretreatment of butyric acid-sensitized Jurkat cells with monoclonal antibodies against CD44, VLA-2, and VLA-5, but not LFA-1 and VLA-4, followed by coculture with Gin-1 cells inhibited T-cell adhesion to fibroblasts and increased apoptosis of nonadherent T cells after coculture of gingival fibroblasts and Jurkat cells. These results indicate that T-cell adherence to fibroblasts is enhanced by butyric acid and that butyric acid-induced T-cell apoptosis is down-regulated by T-cell adhesion to gingival fibroblasts through an interaction with the adhesion molecules CD44, VLA-2, and VLA-5 expressed on T cells stimulated with butyric acid.

scholarly journals Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals.

1995 ◽  
Vol 181 (6) ◽  
pp. 2029-2036 ◽  
Author(s):  
P D Katsikis ◽  
E S Wunderlich ◽  
C A Smith ◽  
L A Herzenberg ◽  
L A Herzenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Apoptosis ◽  
Cd4 T Cell ◽  
Tnf Receptor ◽  
Hiv Disease ◽  
T Cell Apoptosis ◽  
Immunodeficiency Virus ◽  
Induced Apoptosis

Apoptosis (programmed cell death) of T lymphocytes has been proposed as a mechanism which plays an important role in the pathogenesis of human immunodeficiency virus (HIV) disease. Activation of Fas (CD95) can either result in costimulation of proliferation and cytokine production or in the induction of apoptosis of T lymphocytes. This raises the possibility that Fas is involved in the observed T cell apoptosis during HIV disease. In this report we show that peripheral blood CD4+ and CD8+ T lymphocytes from HIV-infected individuals undergo apoptosis in vitro in response to antibody stimulation (cross-linking) of Fas at a much higher frequency than from uninfected controls. This anti-Fas-induced T cell apoptosis is markedly higher than spontaneous T cell apoptosis in HIV-infected individuals. Antibodies against other members of the tumor necrosis factor (TNF)/nerve growth factor receptor family such as CD27, CD30, CD40, 4-1BB, p55 TNF receptor, p75 TNF receptor, and TNF receptor-related protein did not result in any increase of T cell apoptosis above that spontaneously observed in HIV+ individuals. Anti-Fas-induced apoptosis was much higher in symptomatic HIV-infected individuals; and the magnitude of anti-Fas-induced CD4+ T cell apoptosis correlated inversely with peripheral blood CD4+ T cell absolute counts. Surface expression of Fas on T cells was also found to be higher in HIV-infected individuals. Resting and activated CD4+ and CD8+ T cells both underwent apoptosis in response to anti-Fas antibody. L-Selectin positive memory CD4+ T cells were especially susceptible to anti-Fas-induced apoptosis. These findings show that CD4+ and CD8+ T lymphocytes in HIV-infected individuals are primed in vivo to undergo apoptosis in response to Fas stimulation, suggesting that Fas signaling may be responsible for the T lymphocyte functional defects and depletion observed in HIV disease.

scholarly journals Mitofusin 2 Promotes Apoptosis of CD4+ T Cells by Inhibiting Autophagy in Sepsis

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Lan Ying ◽  
Guang-Ju Zhao ◽  
You Wu ◽  
He-Liang Ke ◽  
Guang-Liang Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Critical Role ◽  
Cecal Ligation ◽  
Jurkat Cells ◽  
Mitochondrial Outer Membrane ◽  
Pathophysiological Mechanism ◽  
Mitofusin 2 ◽  
T Cell Apoptosis

Apoptosis of CD4+ T cells is a primary pathophysiological mechanism of immune dysfunction in the pathogenesis of sepsis. Mitofusin 2 (Mfn2), an integral mitochondrial outer membrane protein, has been confirmed to be associated with cellular metabolism, proliferation, and apoptosis. The function of Mfn2 in CD4+ T cell apoptosis in sepsis is poorly understood. Here, we discovered increased in vivo Mfn2 expression, autophagy deficiency, and elevated cell apoptosis in murine splenic CD4+ T cells after cecal ligation and puncture (CLP). We also observed almost identical results in splenic CD4+ T cells upon lipopolysaccharide (LPS) stimulation in vitro. Furthermore, overexpression of Mfn2 resulted in impaired autophagy and increased apoptosis in Jurkat cells. Pharmacological inhibition of autophagy with 3-methyladenine enhanced Mfn2 overexpression-induced cell apoptosis. In addition, overexpression of Mfn2 downregulated phorbol myristate acetate (PMA)/ionomycin-, rapamycin- and starvation-induced autophagy in Jurkat T cells. Taken together, these data indicate a critical role of Mfn2 in CD4+ T cell apoptosis in sepsis and the underlying mechanism of autophagy deficiency.

Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2015-2023 ◽  
Author(s):  
Brian R. Gastman ◽  
Daniel E. Johnson ◽  
Theresa L. Whiteside ◽  
Hannah Rabinowich
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Caspase 3 ◽  
Jurkat Cells ◽  
Caspase 8 ◽  
Induced Apoptosis ◽  
Fluoromethyl Ketone

Abstract Our recent studies suggest that human squamous cell carcinoma of the head and neck (SCCHN) is capable of activating an intrinsic mechanism of programmed-cell death in interacting lymphocytes in situ and in vitro. The current study used Jurkat T-cell line as a model to investigate intracellular apoptotic events in T cells interacting with SCCHN. Apoptosis induced in T lymphocytes by tumor cells was in part Fas-mediated, since it was partially, but significantly, inhibited in the presence of anti-Fas ligand Ab or in Fas-resistant Jurkat cells. The synthetic caspase inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and N-benzyloxycarbonyl-Asp-glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK), effectively blocked apoptosis of Jurkat cells co-incubated with SCCHN cell lines, suggesting the involvement of caspases in tumor-induced apoptosis of lymphocytes. Overexpression of CrmA, an inhibitor of caspase-1 and caspase-8, partially inhibited tumor-induced T-cell death. Caspase-8 and caspase-3 were identified as effector molecules in the execution of tumor-induced T-cell death, since the proform enzymes were processed into active subunits during co-incubation of T cells with tumor cells. Furthermore, co-incubation with tumor cells resulted in cleavage of poly(ADP-ribose) polymerase (PARP), a common caspase-3 substrate, and in cleavage of TcR-ζ chain, shown by us to be a T-cell specific caspase-3 substrate. Overexpression of Bcl-2 did not provide protection of T cells from SCCHN-induced DNA degradation. Instead, the Bcl-2 protein was cleaved in the target T cells during their co-incubation with tumor cells. These findings demonstrate that tumor cells can trigger in T lymphocytes caspase-dependent apoptotic cascades, which are not effectively protected by Bcl-2.

Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 301-308 ◽  
Author(s):  
Simone Fulda ◽  
Gudrun Strauss ◽  
Eric Meyer ◽  
Klaus-Michael Debatin
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Leukemia Cell Line ◽  
Receptor Interaction ◽  
Caspase 8 ◽  
Drug Induced ◽  
Signaling Complex ◽  
Cd95 Ligand ◽  
Activation Induced Cell Death ◽  
Induced Apoptosis

Abstract Activation-induced cell death (AICD) in T cells is mediated by CD95 ligand (CD95L)/receptor interaction, which has also been implicated in apoptosis induction by some anticancer agents. In this article we show that both anti-CD3-triggering (AICD) and doxorubicin treatment led to the production of a functionally active CD95L in the CD3+/T-cell receptor-positive (TCR+) T leukemia cell line H9. CD95L-expressing H9 cells killed CD95-sensitive J16 or CEM target cells, but not CD95-resistant CEM or J16 cells overexpressing dominant negative FADD (J16/FADD-DN). By immunoprecipitation, CD95L was physically bound to CD95, suggesting that AICD and doxorubicin-induced apoptosis involve CD95L-mediated CD95 aggregation, thereby triggering the CD95 death pathway. CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death-inducing signaling complex (DISC), resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP. Blocking of the CD95L/receptor interaction by antagonistic antibodies to CD95 or to CD95L also blocked AICD and inhibited the early phase of doxorubicin-induced apoptosis, though cell death induced by doxorubicin eventually proceeded in a CD95-independent manner. These findings may explain some conflicting data on the role of death receptor systems in drug-induced apoptosis. Thus, in cells with an inducible CD95 receptor/ligand system, drug-induced apoptosis may be mediated by CD95L-initiated DISC formation and activation of downstream effector programs similar to AICD in T cells. (Blood. 2000;95:301-308)

Apoptotic elimination of peripheral T lymphocytes in patients with primary intracranial tumors

1999 ◽  
Vol 91 (6) ◽  
pp. 935-946 ◽  
Author(s):  
Lorri A. Morford ◽  
Amy R. Dix ◽  
William H. Brooks ◽  
Thomas L. Roszman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Cell Culture Supernatant ◽  
Cell Mediated Immunity ◽  
U937 Cells ◽  
Activated T Cells ◽  
Content Type ◽  
T Cell Apoptosis ◽  
Fine Print

Object. Patients with gliomas exhibit severe T lymphopenia during the course of the disease. This study was conducted to determine the mechanism(s) responsible for the lymphopenia.Methods. Using two-color fluorescent staining techniques, the authors show that significant numbers of T cells undergo apoptosis in the peripheral blood of patients with gliomas. To determine whether a glioma-derived factor(s) induces this apoptosis, rosette-purified T cells obtained from healthy donors were treated with glioma cell culture supernatant (GCCS) and examined for apoptosis. It is demonstrated that treatment of normal T cells with GCCS induced apoptosis only with concurrent stimulation of the T-cell receptor/CD3 complex. The addition of neutralizing antibodies to interleukin (IL)-10, IL-4, transforming growth factor-α, or tumor necrosis factor-β (lymphotoxin) did not rescue these T cells from apoptosis. Experiments were also conducted in which the degree of monocyte involvement in the induction of T-cell apoptosis was explored. The U937 cells were pretreated for 20 hours with a 1:20 dilution of GCCS. After the removal of GCCS, the U937 cells were cultured in transwell assays with stimulated T cells. Although control U937 cells did not induce apoptosis of the activated T cells, GCCS-pretreated U937 cells induced appreciable apoptosis in normal, stimulated T-cell cultures.Conclusions. These data indicate that one mechanism by which gliomas cause immunosuppressive effects is the induction of monocytes to release soluble factors that promote activated T-cell apoptosis. The loss of activated T cells leads to T lymphopenia and contributes to the deficiencies in cell-mediated immunity that have been observed during testing of glioma patients' immune function.

scholarly journals CD4+CD25+ Regulatory T Cells Resist a Novel Form of CD28- and Fas-Dependent p53-Induced T Cell Apoptosis

2009 ◽  
Vol 184 (1) ◽  
pp. 94-104 ◽  
Author(s):  
Nagendra Singh ◽  
Mutsumi Yamamoto ◽  
Mariko Takami ◽  
Yoichi Seki ◽  
Mayuko Takezaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Apoptosis ◽  
T Cell Apoptosis
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