Mechanisms of L-Selectin-Induced Activation of the Nuclear Factor of Activated T Lymphocytes (NFAT)

2002 ◽  
Vol 291 (2) ◽  
pp. 237-244 ◽  
Author(s):  
Birgit C. Brenner ◽  
Stephanie Kadel ◽  
Sergei Grigorovich ◽  
Otwin Linderkamp
Keyword(s):  
T Lymphocytes ◽  
Nuclear Factor ◽  
Activated T Lymphocytes

scholarly journals The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-20 ◽  
Author(s):  
Maulilio John Kipanyula ◽  
Wahabu Hamisi Kimaro ◽  
Paul F. Seke Etet
Keyword(s):  
Nervous System ◽  
T Lymphocytes ◽  
Neurodegenerative Diseases ◽  
Psychotic Disorders ◽  
Spinal Cord Injuries ◽  
Metabolic Diseases ◽  
Nuclear Factor ◽  
Activated T Lymphocytes ◽  
Endogenous Regulators ◽  
Brain And Spinal Cord

The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, andα-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

scholarly journals Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium

2005 ◽  
Vol 389 (2) ◽  
pp. 527-539 ◽  
Author(s):  
Shasi V. Kalivendi ◽  
Eugene A. Konorev ◽  
Sonya Cunningham ◽  
Sravan K. Vanamala ◽  
Eugene H. Kaji ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
T Lymphocytes ◽  
Fas Ligand ◽  
Reactive Oxygen ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Rat Cardiomyocytes ◽  
Activated T Lymphocytes ◽  
Pre Treatment ◽  
Fas L

Doxorubicin (DOX), a widely used antitumour drug, causes dose-dependent cardiotoxicity. Cardiac mitochondria represent a critical target organelle of toxicity during DOX chemotherapy. Proposed mechanisms include generation of ROS (reactive oxygen species) and disturbances in mitochondrial calcium homoeostasis. In the present study, we probed the mechanistic link between mitochondrial ROS and calcium in the embryonic rat heart-derived H9c2 cell line and in adult rat cardiomyocytes. The results show that DOX stimulates calcium/calcineurin-dependent activation of the transcription factor NFAT (nuclear factor of activated T-lymphocytes). Pre-treatment of cells with an intracellular calcium chelator abrogated DOX-induced nuclear NFAT translocation, Fas L (Fas ligand) expression and caspase activation, as did pre-treatment of cells with a mitochondria-targeted antioxidant, Mito-Q (a mitochondria-targeted antioxidant consisting of a mixture of mitoquinol and mitoquinone), or with adenoviral-over-expressed antioxidant enzymes. Treatment with GPx-1 (glutathione peroxidase 1), MnSOD (manganese superoxide dismutase) or a peptide inhibitor of NFAT also inhibited DOX-induced nuclear NFAT translocation. Pre-treatment of cells with a Fas L neutralizing antibody abrogated DOX-induced caspase-8- and -3-like activities during the initial stages of apoptosis. We conclude that mitochondria-derived ROS and calcium play a key role in stimulating DOX-induced ‘intrinsic and extrinsic forms’ of apoptosis in cardiac cells with Fas L expression via the NFAT signalling mechanism. Implications of ROS- and calcium-dependent NFAT signalling in DOX-induced apoptosis are discussed.

scholarly journals Mildly oxidized low-density lipoproteins decrease early production of interleukin 2 and nuclear factor κB binding to DNA in activated T-lymphocytes

1999 ◽  
Vol 337 (2) ◽  
pp. 269-274 ◽  
Author(s):  
Sylvie CASPAR-BAUGUIL ◽  
Jean TKACZUK ◽  
Marie-José HAURE ◽  
Martine DURAND ◽  
Julie ALCOUFFE ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Active Form ◽  
Nuclear Factor Κb ◽  
Low Density Lipoproteins ◽  
Receptor Expression ◽  
Low Density ◽  
Nuclear Factor ◽  
Oxidized Low Density Lipoproteins ◽  
Activated T Lymphocytes

Activated T-lymphocytes are found early in atherosclerosis lesions, but little is known about their role. Oxidized low-density lipoproteins (oxLDLs) are considered to be involved in the pathogenesis of the lesions, and we have previously demonstrated that oxLDLs inhibit not only interleukin (IL)-2-receptor expression on the surface of in vitro-activated T-lymphocytes but also their proliferation. We have now investigated the effect of oxLDLs on blast differentiation, on IL-2 synthesis and on the activation of the nuclear factor κB (NF-κB) system in activated lymphocytes. Mildly oxLDLs (50 and 100 µg/ml) decreased the number of lymphoblasts and the level of IL-2 concentration in the culture supernatants after activation of lymphocytes by phytohaemagglutinin and PMA+ionomycin. The inhibition of IL-2 production was observed in the CD3+ T-lymphocyte cytoplasm as early as 4 h after activation by PMA+ionomycin. The study of NF-κB showed that oxLDLs led to a decrease of activation-induced p65/p50 NF-κB heterodimer binding to DNA, whereas the presence of the constitutive nuclear form of p50 dimer was unchanged. This was correlated with an unchanged level of the active form of the cytosolic inhibitor protein IκB-α. Taken together, these observations suggest that the immunosuppressive effect of oxLDLs might operate via a dysregulation of the T-lymphocyte activation mechanisms.

scholarly journals Interleukin-7 Upregulates the Interleukin-2–Gene Expression in Activated Human T Lymphocytes at the Transcriptional Level by Enhancing the DNA Binding Activities of Both Nuclear Factor of Activated T Cells and Activator Protein-1

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2690-2700 ◽  
Author(s):  
Sonja I. Gringhuis ◽  
Lou F.M.H. de Leij ◽  
Emmy W. Verschuren ◽  
Peter Borger ◽  
Edo Vellenga
Keyword(s):  
T Lymphocytes ◽  
Dna Binding ◽  
Binding Activity ◽  
Transcriptional Level ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activated T Cells ◽  
Dna Binding Activity ◽  
Interleukin 7 ◽  
Activated T Lymphocytes

Abstract In the present report, we studied the role of the stromal-derived cytokine interleukin-7 (IL-7) in the IL-2–gene regulation in activated T lymphocytes. Production of IL-2 requires the formation of transcription factors involved in the IL-2 –gene regulation. T-cell receptor (TCR)/CD3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor κB (NFκB), whereas the CD28 responsive complex (CD28RC) is activated in response to the CD28 signal. Costimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhanced IL-2–mRNA accumulation and a 2.5-fold enhanced protein secretion. The IL-2–gene transcription rate is increased 3.4-fold, indicating that the effect of IL-7 is in part mediated at the transcriptional level. The molecular mechanisms underlying the IL-7 effect involve the upregulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), without affecting the activities of NFκB and CD28RC, which was confirmed by transfection assays. We also show that the IL-7–induced enhancement of the AP-1–DNA binding activity is not cyclosporin A-sensitive. Since AP-1 is part of the NFAT complex, we conclude that the IL-7–signaling pathway is involved in the activation of the fos and jun proteins of which AP-1 consists.

scholarly journals Interleukin-7 Upregulates the Interleukin-2–Gene Expression in Activated Human T Lymphocytes at the Transcriptional Level by Enhancing the DNA Binding Activities of Both Nuclear Factor of Activated T Cells and Activator Protein-1

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2690-2700 ◽  
Author(s):  
Sonja I. Gringhuis ◽  
Lou F.M.H. de Leij ◽  
Emmy W. Verschuren ◽  
Peter Borger ◽  
Edo Vellenga
Keyword(s):  
T Lymphocytes ◽  
Dna Binding ◽  
Binding Activity ◽  
Transcriptional Level ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activated T Cells ◽  
Dna Binding Activity ◽  
Interleukin 7 ◽  
Activated T Lymphocytes

In the present report, we studied the role of the stromal-derived cytokine interleukin-7 (IL-7) in the IL-2–gene regulation in activated T lymphocytes. Production of IL-2 requires the formation of transcription factors involved in the IL-2 –gene regulation. T-cell receptor (TCR)/CD3 engagement results in the activation of nuclear factor of activated T cells (NFAT), activator protein-1 (AP-1), and nuclear factor κB (NFκB), whereas the CD28 responsive complex (CD28RC) is activated in response to the CD28 signal. Costimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with IL-7 induces a fivefold enhanced IL-2–mRNA accumulation and a 2.5-fold enhanced protein secretion. The IL-2–gene transcription rate is increased 3.4-fold, indicating that the effect of IL-7 is in part mediated at the transcriptional level. The molecular mechanisms underlying the IL-7 effect involve the upregulation of the DNA binding activity of NFAT (60%) and AP-1 (120%), without affecting the activities of NFκB and CD28RC, which was confirmed by transfection assays. We also show that the IL-7–induced enhancement of the AP-1–DNA binding activity is not cyclosporin A-sensitive. Since AP-1 is part of the NFAT complex, we conclude that the IL-7–signaling pathway is involved in the activation of the fos and jun proteins of which AP-1 consists.

Sign in / Sign up

Export Citation Format

Share Document