Bcl-2 does not inhibit cell death induced by the physiological Fas ligand: implications for the existence of type I and type II cells

Fas, a type I membrane receptor protein, transduces a signal culminating in apoptosis after binding to the Fas ligand. Information regarding the expression of Fas in nonlymphoid tissues, although limited, suggests a role for Fas in epithelial progenitor cell populations. In this paper, we provide several lines of evidence indicating that the progenitor cell of the alveolus, the type II cell, displays restricted expression of Fas. We found 1) Fas gene expression in RNA derived from fresh isolates of primary rat type II cells; 2) restriction of Fas expression to a subset of alveolar type II cells by in situ hybridization and immunohistochemistry of the normal mouse lung; 3) induction of apoptosis in a mouse lung type II epithelial cell line (MLE) after activation of Fas; and 4) induction of apoptosis in a subpopulation of type II cells after the intratracheal instillation of an activating anti-Fas antibody in mice. These findings suggest that Fas-dependent apoptosis is involved in regulating turnover of the alveolar epithelium.

Download Full-text

Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells

Biochemical Journal ◽

10.1042/bj20071704 ◽

2008 ◽

Vol 413 (3) ◽

pp. 467-478 ◽

Cited By ~ 19

Author(s):

Paola Matarrese ◽

Valeria Manganelli ◽

Tina Garofalo ◽

Antonella Tinari ◽

Lucrezia Gambardella ◽

...

Keyword(s):

Cell Death ◽

Cross Talk ◽

Fas Ligand ◽

Type Ii Cells ◽

Type Ii ◽

Ligand Interaction ◽

Directional Movement ◽

Type Ii Cell ◽

Endocytic Vesicles

Participation of diverse organelles in the intracellular signalling that follows CD95/Fas receptor ligation encompasses a series of subcellular changes that are mandatory for, or even bolster, the apoptotic cascade. In the present study, we analysed the role of endocytosis in the propagation of cell death signalling after CD95/Fas engagement in type II cells (CEM cells). We show that this receptor–ligand interaction triggers endocytosis independently of any caspase activation. This FasL (Fas ligand)-induced endocytosis also leads to an early and directional ‘movement’ of endocytic vesicles towards the mitochondrial compartment. In turn, this cross-talk between endosomal and mitochondrial compartments was followed by the loss of the mitochondrial membrane potential and apoptosis execution. This cell remodelling was absent in receptor-independent cell death, such as that induced by the mitochondriotropic drug staurosporine, and in a CEM cell line selected for its multidrug resistance (CEM VBL100). In these cells a reduced FasL (Fas ligand)-induced endocytosis and a reduced organelle cross-talk corresponded to a reduced apoptosis. Altogether, these findings suggest a key role of endocytosis in the propagation and amplification of the CD95/Fas-activated signalling leading to type II cell demise.

Download Full-text

STEM-09. INTRINSIC INTERFERON SIGNALING REGULATES THE CELL DEATH OF GLIOBLASTOMA STEM CELLS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.826 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii198-ii198

Author(s):

Sabbi Khan Khan ◽

Emmanuel Martinez-Ledesma ◽

Sandeep Mittal ◽

Kaitlin Gandy ◽

Kristin Alfaro-Munoz ◽

...

Keyword(s):

Cell Death ◽

Treatment Resistance ◽

Primary Brain Tumor ◽

The Cancer Genome Atlas ◽

Cytokine Signaling ◽

Type I ◽

Type Ii ◽

Mechanistic Investigation ◽

Differential Cell ◽

Stat1 Signaling

Abstract Glioblastoma (GBM) is the most common, highly aggressive, and lethal primary brain tumor in adults. Interferon (IFN)-mediated signal transducer and activator of transcription 1 (STAT1) signaling contributes to various aspects of stemness, cell death, cytokine signaling in immune and non-immune cells. However, the role of IFN/STAT1 signaling in stemness, cell death and treatment resistance in GBM is unclear. This study aimed to investigate the cancer cell-intrinsic IFN/STAT1 signaling and its role in cell proliferation, stemness, and apoptosis. By using the metagene scores for type I and type II IFN-responsive genes, we evaluated basal IFN/STAT1 signaling in The Cancer Genome Atlas (TCGA) and in patient-derived cohorts of stem-like cells (GSCs) RNA expression datasets. In-silico analyses were further validated for the constitutive IFN signaling in a subset of GSCs using qPCR, WB and ELISA assays. We employed pharmacological activators and/or inhibitors of IFN/STAT1 signaling in GSCs to study its role in stemness and cell death. We found differential cell-intrinsic type I and type II IFN-signaling markers in GSCs and GBM tumors. High IFN-signaling is associated with mesenchymal phenotype and poor survival outcomes. Acute and chronic GSC exposure to recombinant IFNs reversibly activated both type I and II IFN-signaling in GSCs. IFN-β exposure induced apoptosis in intrinsically high IFN/STAT1-signaling GSCs, but not in the low IFN/STAT1-signaling GSCs. In summary, our findings demonstrate that GBM exhibit differential cell-intrinsic IFN-signaling, and basal IFN/STAT1 is a key factor for IFN-β-mediated cell death in GSCs. However, further mechanistic investigation of intrinsic IFN signaling in GBM, particularly in the stem cell compartment is needed.

Download Full-text

CD95 death-inducing signaling complex formation and internalization occur in lipid rafts of type I and type II cells

European Journal of Immunology ◽

10.1002/eji.200324786 ◽

2004 ◽

Vol 34 (7) ◽

pp. 1930-1940 ◽

Cited By ~ 77

Author(s):

Adriana Eramo ◽

Massimo Sargiacomo ◽

Lucia Ricci-Vitiani ◽

Matilde Todaro ◽

Giorgio Stassi ◽

...

Keyword(s):

Complex Formation ◽

Lipid Rafts ◽

Type I ◽

Type Ii Cells ◽

Type Ii ◽

Signaling Complex

Download Full-text

The Roles Potassium Currents Play in Regulating the Electrical Activity of Ventral Cochlear Nucleus Neurons

Journal of Neurophysiology ◽

10.1152/jn.00127.2002 ◽

2003 ◽

Vol 89 (6) ◽

pp. 3097-3113 ◽

Cited By ~ 180

Author(s):

Jason S. Rothman ◽

Paul B. Manis

Keyword(s):

Cochlear Nucleus ◽

Auditory Nerve ◽

Threshold Current ◽

Repetitive Firing ◽

Resting Membrane Potential ◽

Type I ◽

Type Ii Cells ◽

Type Ii ◽

Ventral Cochlear Nucleus ◽

Discharge Patterns

Using kinetic data from three different K+ currents in acutely isolated neurons, a single electrical compartment representing the soma of a ventral cochlear nucleus (VCN) neuron was created. The K+ currents include a fast transient current ( IA), a slow-inactivating low-threshold current ( ILT), and a noninactivating high-threshold current ( IHT). The model also includes a fast-inactivating Na+ current, a hyperpolarization-activated cation current ( Ih), and 1–50 auditory nerve synapses. With this model, the role IA, ILT, and IHT play in shaping the discharge patterns of VCN cells is explored. Simulation results indicate that IHT mainly functions to repolarize the membrane during an action potential, and IA functions to modulate the rate of repetitive firing. ILT is found to be responsible for the phasic discharge pattern observed in Type II cells (bushy cells). However, by adjusting the strength of ILT, both phasic and regular discharge patterns are observed, demonstrating that a critical level of ILT is necessary to produce the Type II response. Simulated Type II cells have a significantly faster membrane time constant in comparison to Type I cells (stellate cells) and are therefore better suited to preserve temporal information in their auditory nerve inputs by acting as precise coincidence detectors and having a short refractory period. Finally, we demonstrate that modulation of Ih, which changes the resting membrane potential, is a more effective means of modulating the activation level of ILT than simply modulating ILT itself. This result may explain why ILT and Ih are often coexpressed throughout the nervous system.

Download Full-text

Disparate cytokine regulation of ICAM-1 in rat alveolar epithelial cells and pulmonary endothelial cells in vitro

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1995.269.1.l127 ◽

1995 ◽

Vol 269 (1) ◽

pp. L127-L135 ◽

Cited By ~ 5

Author(s):

W. W. Barton ◽

S. Wilcoxen ◽

P. J. Christensen ◽

R. Paine

Keyword(s):

Endothelial Cells ◽

Epithelial Cells ◽

Inflammatory Cytokines ◽

Alveolar Epithelial Cells ◽

Normal Lung ◽

Type I ◽

Type Ii Cells ◽

Type Ii ◽

Alveolar Epithelial

Intercellular adhesion molecule-1 (ICAM-1) is expressed at high levels on type I alveolar epithelial cells in the normal lung and is induced in vitro as type II cells spread in primary culture. In contrast, in most nonhematopoetic cells ICAM-1 expression is induced in response to inflammatory cytokines. We have formed the hypothesis that the signals that control ICAM-1 expression in alveolar epithelial cells are fundamentally different from those controlling expression in most other cells. To test this hypothesis, we have investigated the influence of inflammatory cytokines on ICAM-1 expression in isolated type II cells that have spread in culture and compared this response to that of rat pulmonary artery endothelial cells (RPAEC). ICAM-1 protein, determined both by a cell-based enzyme-linked immunosorbent assay and by Western blot analysis, and mRNA were minimally expressed in unstimulated RPAEC but were significantly induced in a time- and dose-dependent manner by treatment with tumor necrosis factor-alpha, interleukin-1 beta, or interferon-gamma. In contrast, these cytokines did not influence the constitutive high level ICAM-1 protein expression in alveolar epithelial cells and only minimally affected steady-state mRNA levels. ICAM-1 mRNA half-life, measured in the presence of actinomycin D, was relatively long at 7 h in alveolar epithelial cells and 4 h in RPAEC. The striking lack of response of ICAM-1 expression by alveolar epithelial cells to inflammatory cytokines is in contrast to virtually all other epithelial cells studied to date and supports the hypothesis that ICAM-1 expression by these cells is a function of cellular differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Sulfation of extracellular matrices modifies responses of alveolar type II cells to fibroblast growth factors

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1996.271.5.l688 ◽

1996 ◽

Vol 271 (5) ◽

pp. L688-L697 ◽

Cited By ~ 9

Author(s):

P. L. Sannes ◽

J. Khosla ◽

P. W. Cheng

Keyword(s):

Growth Factors ◽

Biological Significance ◽

Alveolar Type ◽

Type I ◽

Type Ii Cells ◽

Type Ii ◽

Fibroblast Growth ◽

Alveolar Type Ii Cells ◽

Proliferation And Differentiation ◽

Type Ii Cell

The pulmonary alveolar basement membrane (BM) associated with alveolar type II cells has been shown to be significantly less sulfated than that of type I cells. To examine the biological significance of this observation, we measured the incorporation of 5-bromodeoxyuridine (BrdU) as an indicator of DNA synthesis in isolated rat type II cells cultured for 72-120 h on substrata that were naturally sulfated, not sulfated, or chemically desulfated in serum-free, hormonally defined media, with and without selected growth factors. The percentage of cells incorporating BrdU was significantly elevated by desulfated chondroitin sulfate in the presence of fibroblast growth factor-2 (FGF-2 or basic FGF) and depressed by heparin in the presence of either FGF-1 or acidic FGF or FGF-2. This depressive effect was lost by removing sulfate from the heparin. Some responses were dependent on the period of time in culture and concentration and molecular weight of the substrata. These observations support the notion that sulfation per se of certain components of BM is a key determinant of type II cell responses to select growth factors that may define patterns of proliferation and differentiation.

Download Full-text