scholarly journals Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase

2000 ◽  
Vol 191 (6) ◽  
pp. 1017-1030 ◽  
Author(s):  
Jian Zhang ◽  
Jian-Xin Gao ◽  
Kostantin Salojin ◽  
Qing Shao ◽  
Marsha Grattan ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Mitogen Activated Protein Kinase ◽  
Fasl Expression ◽  
Activation Induced Cell Death ◽  
Mitogen Activated Protein

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates the Fas-Induced Mitochondrial Death Pathway in CD8+ T Cells

2006 ◽  
Vol 26 (6) ◽  
pp. 2118-2129 ◽  
Author(s):  
Nicholas Farley ◽  
Gustavo Pedraza-Alva ◽  
Diego Serrano-Gomez ◽  
Viswas Nagaleekar ◽  
Alexander Aronshtam ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Death Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Mitochondrial Death Pathway ◽  
Induced Apoptosis

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated by a variety of stress stimuli such as UV radiation and osmotic stress. The regulation and role of this pathway in death receptor-induced apoptosis remain unclear and may depend on the specific death receptor and cell type. Here we show that binding of Fas ligand to Fas activates p38 MAPK in CD8+ T cells and that activation of this pathway is required for Fas-mediated CD8+ T-cell death. Active p38 MAPK phosphorylates Bcl-xL and Bcl-2 and prevents the accumulation of these antiapoptotic molecules within the mitochondria. Consequently, a loss of mitochondrial membrane potential and the release of cytochrome c lead to the activation of caspase 9 and, subsequently, caspase 3. Therefore, the activation of p38 MAPK is a critical link between Fas and the mitochondrial death pathway and is required for the Fas-induced apoptosis of CD8+ T cells.

scholarly journals Fas ligand mediates activation-induced cell death in human T lymphocytes.

1995 ◽  
Vol 181 (1) ◽  
pp. 71-77 ◽  
Author(s):  
M R Alderson ◽  
T W Tough ◽  
T Davis-Smith ◽  
S Braddy ◽  
B Falk ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Fas Ligand ◽  
Significant Proportion ◽  
Cell Receptor ◽  
Target Cells ◽  
Activated T Cells ◽  
Activation Induced Cell Death ◽  
Fas L

A significant proportion of previously activated human T cells undergo apoptosis when triggered through the CD3/T cell receptor complex, a process termed activation-induced cell death (AICD). Ligation of Fas on activated T cells by either Fas antibodies or recombinant human Fas-ligand (Fas-L) also results in cytolysis. We demonstrate that these two pathways of apoptosis are causally related. Stimulation of previously activated T cells resulted in the expression of Fas-L mRNA and lysis of Fas-positive target cells. Fas-L antagonists inhibited AICD of T cell clones and staphylococcus enterotoxin B (SEB)-specific T cell lines. The data indicate AICD in previously stimulated T cells is mediated by Fas/Fas-L interactions.

p38 MAPK Mediates Inhibition of Activation Induced Cell Death in T Lymphocytes Via Upregulation of Bcl-xL and FLIPshort upon Ligation of CD137/4-1BB or CD28.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3320-3320
Author(s):  
Christian Scholz ◽  
Lilian Stärck ◽  
Mario Lehmann ◽  
Bernd Dörken ◽  
Peter T. Daniel
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
Family Member ◽  
P38 Mapk ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activation Induced Cell Death ◽  
Costimulatory Signals

Abstract Costimulation is essential for the induction of proliferation in naive T cells and for the inhibition of activation induced cell death (AICD) in activated T lymphocytes. While costimulatory signals mediated through the immunglobulin family member CD28 play a prominent role during primary T cell activation, ligation of the tumor necrosis factor receptor family member CD137/4-1BB is more important during late primary and secondary T cell activation. Signals mediated through either costimulatory protein block AICD. Inhibition of AICD through ligation of CD137/4-1BB or CD28 involves upregulation of Bcl-xL and FLIPshort (Eur J Immunol 2005, 35: 1257–66). We further demonstrated that costimulatory signals mediated through CD137/4-1BB or CD28 depend on the activity of phosphatidylinositol 3-kinase and AKT/protein kinase B, two kinases that had formerly been implied in CD28-induced signaling, indicating that CD28- and CD137/4-1BB-mediated signals share downstream signaling pathways. Here, we demonstrate that p38 mitogen-activated protein kinase (MAPK) mediates CD137/4-1BB-induced as well as CD28-mediated costimulation of cell proliferation and inhibition of AICD. This coincides with upregulation of Bcl-xL and FLIPshort. Inhibition of p38 MAPK abrogates T cell receptor induced proliferation and antagonizes costimulation mediated survival. Thus, p38 MAPK, which was previously thought to be primarily involved in CD137/4-1BB-mediated signaling, is similarly important for CD28-induced costimulation and survival. This indicates that, while involving different protein families, signal transduction by CD28 and CD137/4-1BB depends on a common upstream and downstream network of survival kinases.

Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 617-625 ◽  
Author(s):  
Sven Baumann ◽  
Anja Dostert ◽  
Natalia Novac ◽  
Anton Bauer ◽  
Wolfgang Schmid ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Glucocorticoid Receptor ◽  
Fas Ligand ◽  
Regulatory Elements ◽  
Activated T Cells ◽  
Activation Induced Cell Death

Abstract Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs. (Blood. 2005;106:617-625)

scholarly journals FAS Ligand, Bcl-2, Granulocyte Colony-Stimulating Factor, and p38 Mitogen-Activated Protein Kinase

2000 ◽  
Vol 192 (5) ◽  
pp. 647-658 ◽  
Author(s):  
Andreas Villunger ◽  
Lorraine A. O'Reilly ◽  
Nils Holler ◽  
Jerry Adams ◽  
Andreas Strasser
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Fas Ligand ◽  
Mitogen Activated Protein Kinase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Stimulating Factor

The short life span of granulocytes, which limits many inflammatory responses, is thought to be influenced by the Bcl-2 protein family, death receptors such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), and proinflammatory cytokines like granulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spontaneous apoptosis of granulocytes in culture and that induced by Fas ligand or chemotherapeutic drugs, using cells from normal, CD95-deficient lpr, or vav-bcl-2 transgenic mice. CD95-induced apoptosis, which required receptor aggregation by recombinant Fas ligand or the membrane-bound ligand, was unaffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in lpr granulocytes but were suppressed by G-CSF treatment or Bcl-2 overexpression. Although activation of p38 MAPK has been implicated in granulocyte death, their apoptosis actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Bcl-2–controlled pathway, whereas CD95 regulates a distinct pathway to apoptosis that is not required for either their spontaneous or drug-induced death. Moreover, p38 MAPK signaling contributes to granulocyte survival rather than their apoptosis.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest

2003 ◽  
Vol 14 (5) ◽  
pp. 2071-2087 ◽  
Author(s):  
Karl Deacon ◽  
Pratibha Mistry ◽  
Jonathan Chernoff ◽  
Jonathan L. Blank ◽  
Rajnikant Patel
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Survival ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Chemotherapeutic Drugs ◽  
Chemotherapeutic Drug ◽  
Drug Induced ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase

Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death.

scholarly journals Nuclear Factor of Activated T Cells c Is a Target of p38 Mitogen-Activated Protein Kinase in T Cells

2003 ◽  
Vol 23 (18) ◽  
pp. 6442-6454 ◽  
Author(s):  
Chia-Cheng Wu ◽  
Shu-Ching Hsu ◽  
Hsiu-ming Shih ◽  
Ming-Zong Lai
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
P38 Mapk ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Factor ◽  
Creb Binding Protein ◽  
Activated T Cells ◽  
Mitogen Activated Protein

ABSTRACT p38 mitogen activated protein kinase (MAPK) is essential for T-cell activation. Here we demonstrated that nuclear factor of activated T cells (NFAT) is a direct target of p38 MAPK. Inhibition of p38 MAPK led to selective inactivation of NFAT in T cells. We further linked a strict requirement of p38 MAPK to activation of NFATc. A stimulatory effect of p38 MAPK on at least four other stages of NFATc activation was found. First, the p38 MAPK cascade activated the NFATc promoter and induced the transcription of NFATc mRNA. Second, p38 MAPK mildly increased the mRNA stability of NFATc. Third, p38 MAPK enhanced the translation of NFATc mRNA. Fourth, p38 MAPK promoted the interaction of NFATc with the coactivator CREB-binding protein. In contrast, p38 MAPK moderately enhanced the expulsion of NFATc from the nucleus in T cells. Therefore, p38 MAPK has opposite effects on different stages of NFATc activation. All together, the overall effect of p38 MAPK on NFATc in T cells is clear activation.

scholarly journals KSR1 Modulates the Sensitivity of Mitogen-Activated Protein Kinase Pathway Activation in T Cells without Altering Fundamental System Outputs

2009 ◽  
Vol 29 (8) ◽  
pp. 2082-2091 ◽  
Author(s):  
Joseph Lin ◽  
Angus Harding ◽  
Emanuele Giurisato ◽  
Andrey S. Shaw
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cell Fate Decisions ◽  
Mapk Cascades ◽  
Wide Range ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that regulate cell fate decisions. They generate a wide range of signal outputs, including graded and digital responses. In T cells, MAPK activation is digital in response to T-cell-receptor stimulation; however, whether other receptors on T cells that lead to MAPK activation are graded or digital is unknown. Here we evaluate MAPK activation in T cells at the single-cell level. We show that T cells responded digitally to stimulation with superantigen-loaded antigen-presenting cells, whereas they responded in a graded manner to the chemokine SDF-1, demonstrating that the system output of the MAPK module is highly plastic and determined by components upstream of the MAPK module. These findings also confirm that different MAPK system outputs are used by T cells to control discrete biological functions. Scaffold proteins are essential for proper MAPK signaling and function as they physically assemble multiple components and regulators of MAPK cascades. We found that the scaffold protein KSR1 regulated the threshold required for MAPK activation in T cells without affecting the nature of the response. We conclude that KSR1 plays a central role in determining the sensitivity of T-cell responses and is thus well positioned as a key control point.

Engagement of the α2β1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2044-2051 ◽  
Author(s):  
Fawzi Aoudjit ◽  
Kristiina Vuori
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Fas Ligand ◽  
Integrin Signaling ◽  
Activation Induced Cell Death ◽  
Fas L

Abstract T-cell receptor (TCR)-mediated apoptosis, also known as activation-induced cell death (AICD), plays an important role in the control of immune response and in the development of T-cell repertoire. Mechanistically, AICD has been largely attributed to the interaction of Fas ligand (Fas-L) with its cell surface receptor Fas in activated T cells. Signal transduction mediated by the integrin family of cell adhesion receptors has been previously shown to modulate apoptosis in a number of different cell types; in T cells, integrin signaling is known to be important in cellular response to antigenic challenge by providing a co-stimulatory signal for TCR. In this study we demonstrate that signaling via the collagen receptor 2β1 integrin specifically inhibits AICD by inhibiting Fas-L expression in activated Jurkat T cells. Engagement of the 2β1 integrin with monoclonal antibodies or with type I collagen, a cognate ligand for 2β1, reduced anti-CD3 and PMA/ionomycin-induced cell death by 30% and 40%, respectively, and the expression of Fas-L mRNA by 50%. Further studies indicated that the 2β1-mediated inhibition of AICD and Fas-L expression required the focal adhesion kinase FAK, a known component in the integrin signaling pathways. These results suggest a role for the 2β1 integrin in the control of homeostasis of immune response and T-cell development.

Sign in / Sign up

Export Citation Format

Share Document