Search results for " signaling."
showing 10 items of 1032 documents
SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth.
2013
Abstract Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4…
MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4
2015
A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functi…
Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocyte-derived…
2000
Abstract Dendritic cell (DC) vaccination, albeit still in an early stage, is a promising strategy to induce immunity to cancer. We explored whether DC can expand Ag-specific CD8+ T cells even in far-advanced stage IV melanoma patients. We found that three to five biweekly vaccinations of mature, monocyte-derived DC (three vaccinations of 6 × 106 s.c. followed by two i.v. ones of 6 and 12 × 106, respectively) pulsed with Mage-3A2.1 tumor and influenza matrix A2.1-positive control peptides as well as the recall Ag tetanus toxoid (in three of eight patients) generated in all eight patients Ag-specific effector CD8+ T cells that were detectable in blood directly ex vivo. This is the first time …
Cutting Edge: TGF-β Induces a Regulatory Phenotype in CD4+CD25− T Cells through Foxp3 Induction and Down-Regulation of Smad7
2004
Abstract CD4+CD25+ regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-β is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4+CD25− peripheral murine T cells. Similarly, TGF-β induced Foxp3 in human CD4+CD25− T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-β and limits TGF-β signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4+CD2…
Docosahexaenoic acid modulates the expression of T-bet and GATA-3 transcription factors, independently of PPARα, through suppression of MAP kinase ac…
2009
The present study was conducted on CD4(+) T cells, isolated from wild type (WT) and PPARalpha(null) mice, in order to assess the mechanism of action of docosahexaenoic acid (DHA), an n-3 fatty acid, in the modulation of two transcription factors, i.e., T-bet and GATA-3, implicated in T-cell differentiation towards, respectively, T(H)1 and T(H)2 phenotype. The T-cells from PPARalpha(null) mice secreted higher IFN-gamma and lower IL-4 concentrations than WT T-cells. Furthermore, the deletion of PPARalpha gene in T-cells resulted in the upregulation of T-bet and downregulation of GATA-3 both at mRNA and protein levels. DHA exerted not only an inhibitory effect on T-cell proliferation, but also…
Tracking Ca2+ ATPase intermediates in real time by x-ray solution scattering
2020
Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) transporters regulate calcium signaling by active calcium ion reuptake to internal stores. Structural transitions associated with transport have been characterized by x-ray crystallography, but critical intermediates involved in the accessibility switch across the membrane are missing. We combined time-resolved x-ray solution scattering (TR-XSS) experiments and molecular dynamics (MD) simulations for real-time tracking of concerted SERCA reaction cycle dynamics in the native membrane. The equilibrium [Ca2] E1 state before laser activation differed in the domain arrangement compared with crystal structures, and following laser-induced release o…
Postsynaptic Secretion of BDNF and NT-3 from Hippocampal Neurons Depends on Calcium–Calmodulin Kinase II Signaling and Proceeds via Delayed Fusion Po…
2007
The mammalian neurotrophins (NTs) NGF, BDNF, NT-3, and NT-4 constitute a family of secreted neuronal growth factors. In addition, NTs are implicated in several forms of activity-dependent synaptic plasticity. Although synaptic secretion of NTs has been described, the intracellular signaling cascades that regulate synaptic secretion of NTs are far from being understood. Analysis of NT secretion at the subcellular level is thus required to resolve the role of presynaptic and postsynaptic NT secretion for synaptic plasticity. Here, we transfected cultures of dissociated rat hippocampal neurons with green fluorescent protein-tagged versions of BDNF and NT-3, respectively, and identified NT vesi…
Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells
2010
MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP- or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34+ cells. These chromatin-modifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential fo…
Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway
2009
In chronic myeloid leukemia, activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is crucial for survival and proliferation of leukemic cells. Essential downstream molecules involve mammalian target of rapamycin (mTOR) and S6-kinase. Here, we present a comprehensive analysis of the molecular events involved in activation of these key signaling pathways. We provide evidence for a previously unrecognized phospholipase C-gamma1 (PLC-gamma1)-controlled mechanism of mTOR/p70S6-kinase activation, which operates in parallel to the classical Akt-dependent machinery. Short-term imatinib treatment of Bcr-Abl-positive cells caused dephosphorylation of p70S6-K and S6-protein without inactivat…
Holo-APP and G-protein-mediated signaling are required for sAPPa-induced activation of the Akt survival pathway
2014
International audience; Accumulating evidence indicates that loss of physiologic amyloid precursor protein (APP) function leads to reduced neuronal plasticity, diminished synaptic signaling and enhanced susceptibility of neurons to cellular stress during brain aging. Here we investigated the neuroprotective function of the soluble APP ectodomain sAPPa (soluble APPa), which is generated by cleavage of APP by a-secretase along the non-amyloidogenic pathway. Recombinant sAPPa protected primary hippocampal neurons and SH-SY5Y neuroblastoma cells from cell death induced by trophic factor deprivation. We show that this protective effect is abrogated in neurons from APP-knockout animals and APP-de…