MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly

Holmström, Tim H.; Schmitz, Ingo; Söderström, Thomas; Poukkula, Minna; Johnson, Victoria L.; Chow, Sek C.; Krammer, Peter H.; Eriksson, John E.

doi:10.1093/emboj/19.20.5418

Cited by 172 publications

(131 citation statements)

References 48 publications

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“…These disparate findings may be related to the fact that these drugs, a psychostimulant vs a psychodepressant, exert opposing effects on the CNS. In fact, opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of the antiapoptotic ERK1/2 signaling pathway (Garcia-Fuster et al, 2007), crucial for protection against Fas/FADD-mediated apoptosis (Holmstrom et al, 1999(Holmstrom et al, , 2000. Other experimental evidence has shown that cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells (Hu et al, 2006).…”

Section: Regulation Of Fadd By Cocaine M-j García-fuster Et Almentioning

confidence: 99%

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

García-Fuster

Clinton

Watson

et al. 2008

Neuropsychopharmacol

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This study was designed to (1) assess the effects of cocaine on Fas-associated protein with death domain (FADD) system and its role in the activation of apoptotic vs nonapoptotic events and (2) ascertain whether animals selectively bred for their differential propensity to drug-seeking show differences in FADD levels or response to cocaine. Acute cocaine, through D 2 dopamine receptors, induced a doseresponse increase in FADD protein in the cortex, with opposite effects over pFADD (Ser191/194), and no induction of apoptotic cell death (poly-(ADP-ribose) polymerase cleavage). FADD was increased by cocaine in cytosol (B142%), membranes (B23%) and nucleus (B54%). The modulation of the FADD system showed tolerance of the acute effect over time, as well as a compensatory response on withdrawal that mirrored the acute effectFie a transient FADD decrease on day 3 of withdrawal, both at mRNA and protein levels. In a second experiment, possible FADD differences were investigated in rats selectively bred for differential responsiveness to novelty, propensity for drug-seeking and cocaine sensitization. High-responders (HR), who were more prone to drug abuse, exhibited higher FADD and lower pFADD levels than low-responder (LR) rats. However, HR and LR rats showed similar rates of cocaine-induced apoptosis, and exhibited a parallel impact of cocaine over FADD within each phenotype. Thus, FADD is a signaling protein modulated by cocaine, regulating apoptosis/proliferative mechanisms in relation to its FADD/pFADD content. Interestingly, animals selectively bred for differential propensity to substance abuse show basal differences in the expression of this protein, suggesting FADD may also be a molecular correlate for the HR/LR phenotype.

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Section: Regulation Of Fadd By Cocaine M-j García-fuster Et Almentioning

confidence: 99%

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

García-Fuster

Clinton

Watson

et al. 2008

Neuropsychopharmacol

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“…Together, the results suggest that possible apoptotic signals engaged by Fas activation (see Tegeder and Geisslinger, 2004;Liao et al, 2005) would be offset by decreased signal transduction through FADD and effector caspases-8/3 (not altered by any opiate treatment). Since the activation of ERK1/2 is crucial for various antiapoptotic mechanisms (Wada and Penninger, 2004), including protection against Fas-mediated apoptosis (Holmström et al, 1999(Holmström et al, , 2000, it is tempting to conclude that opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of ERK1/2 signaling. In this context, recent studies have shown that activation of d-opioid receptors can protect neocortical neurons from glutamate excitotoxicity (Zhang et al, 2000) and induce other cytoprotective effects (Barry and Zuo, 2005).…”

Section: Regulation Of Fadd By Opiate Drugsmentioning

confidence: 99%

“…These nonapoptotic roles for Fas/FADD are still poorly understood and may involve the activation of the ERK1/2 MAPK pathway, which is important for antiapoptotic signals (Holmström et al, 1999(Holmström et al, , 2000Wada and Penninger, 2004) and for the regulation of synaptic plasticity, learning, and memory (Kyosseva, 2004).…”

Section: Introductionmentioning

confidence: 99%

Effects of Opiate Drugs on Fas-Associated Protein with Death Domain (FADD) and Effector Caspases in the Rat Brain: Regulation by the ERK1/2 MAP Kinase Pathway

García-Fuster

Miralles

Garcı́a-Sevilla

2006

Neuropsychopharmacol

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This study was designed to assess the effects of opiate treatment on the expression of Fas-associated protein with death domain (FADD) in the rat brain. FADD is involved in the transmission of Fas-death signals that have been suggested to contribute to the development of opiate tolerance and addiction. Acute treatments with high doses of sufentanil and morphine (m-agonists), , and U50488H (k-agonist) induced significant decreases (30-60%) in FADD immunodensity in the cerebral cortex, through specific opioid receptor mechanisms (effects antagonized by naloxone, naltrindole, or nor-binaltorphimine). The cannabinoid CB 1 receptor agonist WIN 55,212-2 did not alter FADD content in the brain. Chronic (5 days) morphine (10-100 mg/kg), SNC-80 (10 mg/kg), or U50488H (10 mg/kg) was associated with the induction of tachyphylaxis to the acute effects. In morphine-and SNC-80-tolerant rats, antagonistprecipitated (2 h) or spontaneous withdrawal (24-48 h) induced a new and sustained inhibition of FADD (13-50%). None of these treatments altered the densities of caspases 8/3 (including the active cleaved forms) in the brain. Pretreatment of rats with SL 327 (a selective MEK1/2 inhibitor that blocks ERK activation) fully prevented the reduction of FADD content induced by SNC-80 in the cerebral cortex (43%) and corpus striatum (29%), demonstrating the direct involvement of ERK1/2 signaling in the regulation of FADD by the opiate agonist. The results indicate that m-and d-opioid receptors have a prominent role in the modulation of FADD (opposite to that of Fas) shortly after initiating treatment. Opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of the antiapoptotic ERK1/2 signaling pathway.

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“…2 Along this line several reports indicated that TCR triggering protects from CD95-mediated apoptosis. [32][33][34] In the murine system, naïve T cells were reported to die after TCR and CD95 ligation while memory T cells were costimulated and induced to proliferate. 35 However, all systems have in common that stimulation was achieved by monoclonal antibodies instead of APC coexpressing antigen, costimulatory molecules and CD95L on the cell surface.…”

Section: Cd95l Expressed On T Cells Mediates a Dual Functionmentioning

confidence: 99%

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

et al. 2006

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Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4 þ and CD8 þ HLA-A1-specifc T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases. Apoptosis mediated by the CD95 system plays a pivotal regulatory role in the maintenance of immune homeostasis. Deficiency in CD95 or CD95L expression in T cells mediates lymphoproliferative disorders due to the lack of apoptosis induction. 1 Paradoxically, several molecules of the CD95 signaling pathway are also required for T cell activation and proliferation. 2 In addition to T cells, live and death of antigenpresenting cells, which initiate T cell responses has to be tightly controlled to avoid the establishment of autoimmunity. 3 Activation-induced cell death (AICD) represents an apoptosis mechanism mediated via the interaction of CD95 with its ligand CD95L, to mediate T cell death and initiate the termination of an immune response to maintain tolerance to self antigens and to prevent autoimmunity. 4 Owing to the constitutive expression of CD95L in immune privileged organs such as testis or eye, 5,6 CD95L was considered as an immunoprotective agent able to counterattack activated T cells in vivo. However, the role of CD95L in transplantation tolerance is still controversial. While allogeneic pancreatic islands transplanted together with syngeneic CD95L expressing myoblasts were tolerated, 7 allogeneic CD95L expressing pancreatic b cells were rejected due to increased neutrophil infiltration. 8 Lack of immunogenicity of tumors and resistance towards T cell attacks were also correlated with the expression of CD95L on tumor tissues. Such tumors were shown to kill CD95-positive cells in vitro. 9 However, transfection of CD95L into murine tumor cells did not enhance tumor growth, but instead induced accelerated tumor rejection by neutrophils in vivo. [10][11][12] Systemic immunomodulation by CD95L was successfully achieved by antigen-presenting cells modified to express CD95L. 13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models. 14,15 This approach benefits from the hig...

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MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly

Cited by 172 publications

References 48 publications

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

Effects of Opiate Drugs on Fas-Associated Protein with Death Domain (FADD) and Effector Caspases in the Rat Brain: Regulation by the ERK1/2 MAP Kinase Pathway

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

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