13 research outputs found
Low dose ionizing radiation induces morphological and immunological modulation of immune cells
In the present thesis I examine the effect of ionizing radiation on normal and leukemic immune cells. Stimulation of freshly isolated peripheral blood lymphocytes (PBLs) by mitogens like phytohemagglutinin (PHA-L) or by a specific T-cell activator that crosslinks different clusters of differentiation (CD) causes an immune activation. The latter is associated with a strong increase in the cell diameter. In addition the electrophysiological properties and the ion channel composition of the plasma membrane of PBLs are altered. In the present thesis I show that a similar increase in cell diameter occurs in response to irradiation of immune cells with low doses of X-ray. This indicates that ionizing radiation (IR) triggers a signaling cascade, which results in an immunomodulation or activation of PBLs. This irradiation phenomena was studied here in more detail with Jurkat cells, a T-cell progenitor cell line derived from a patient with acute T-cell leukemia, a specific type of acute lymphatic leukemia (ALL).
The data show that IR elicits in these cells a dose dependent increase in cell diameter. The latter is similar to the increase in the cell diameter of PBLs after immune stimulation. The IR induced increase in cell diameter originates from two different sources: one is the IR dependent arrest of the cell cycle in G2, the second one is associated with an immune activation. The second component can also be triggered by external application of hydrogen peroxide (H2O2), a reactive oxygen species (ROS), and inhibited by immunosuppressant drugs like cyclosporine A. The morphological changes in irradiated Jurkat cells are associated with changes in the electrical properties including an upregulation of a calcium dependent potassium channel. Furthermore the expression of the interleukin-2-receptor alpha chain (CD25), which is expressed in activated and regulatory T-cells, was found. Adhesion assays and single molecule microscopy furthermore show that IR also triggers cell-cell and cell-surface adhesion, a process that is mediated by upregulation and clustering of integrin-β-1 due to IR. All these cellular responses to IR are similar to those found in T-cells after immune activation.
The finding that ionizing radiation elicits an increase in cell size in immune cells, enhanced expression of adhesion molecules and altered ion channel composition in the plasma membrane leads to the hypothesis that IR presumably effects an immunological activation or modulation of these cells. This immunomodulation could explain why low dose IR can be beneficial in the treatment of patients suffering from e.g. chronic inflammation and autoimmune diseases like rheumatoid arthritis. Furthermore the finding that integrin-β-1 mediated adhesion is increased in Jurkat cells after IR could be of importance for the clinical treatment of leukemia patients. Here treatment is often a combination of chemotherapy and radiotherapy. On the background of the present data it is possible that radiation treatment could have previously unknown negative side effects. A rise in cell size, an increased adhesion to endothelial tissue as well as changes in the ion channel composition could lead to massive adhesion and transmigration of acute lymphoblastic leukemia (ALL) cells after radiotherapy. Drugs, which suppress specific integrin-β-1 mediated adhesion might reduce such negative side effects
Low dose ionizing radiation induces morphological and immunological modulation of immune cells
In the present thesis I examine the effect of ionizing radiation on normal and leukemic immune cells. Stimulation of freshly isolated peripheral blood lymphocytes (PBLs) by mitogens like phytohemagglutinin (PHA-L) or by a specific T-cell activator that crosslinks different clusters of differentiation (CD) causes an immune activation. The latter is associated with a strong increase in the cell diameter. In addition the electrophysiological properties and the ion channel composition of the plasma membrane of PBLs are altered. In the present thesis I show that a similar increase in cell diameter occurs in response to irradiation of immune cells with low doses of X-ray. This indicates that ionizing radiation (IR) triggers a signaling cascade, which results in an immunomodulation or activation of PBLs. This irradiation phenomena was studied here in more detail with Jurkat cells, a T-cell progenitor cell line derived from a patient with acute T-cell leukemia, a specific type of acute lymphatic leukemia (ALL).
The data show that IR elicits in these cells a dose dependent increase in cell diameter. The latter is similar to the increase in the cell diameter of PBLs after immune stimulation. The IR induced increase in cell diameter originates from two different sources: one is the IR dependent arrest of the cell cycle in G2, the second one is associated with an immune activation. The second component can also be triggered by external application of hydrogen peroxide (H2O2), a reactive oxygen species (ROS), and inhibited by immunosuppressant drugs like cyclosporine A. The morphological changes in irradiated Jurkat cells are associated with changes in the electrical properties including an upregulation of a calcium dependent potassium channel. Furthermore the expression of the interleukin-2-receptor alpha chain (CD25), which is expressed in activated and regulatory T-cells, was found. Adhesion assays and single molecule microscopy furthermore show that IR also triggers cell-cell and cell-surface adhesion, a process that is mediated by upregulation and clustering of integrin-β-1 due to IR. All these cellular responses to IR are similar to those found in T-cells after immune activation.
The finding that ionizing radiation elicits an increase in cell size in immune cells, enhanced expression of adhesion molecules and altered ion channel composition in the plasma membrane leads to the hypothesis that IR presumably effects an immunological activation or modulation of these cells. This immunomodulation could explain why low dose IR can be beneficial in the treatment of patients suffering from e.g. chronic inflammation and autoimmune diseases like rheumatoid arthritis. Furthermore the finding that integrin-β-1 mediated adhesion is increased in Jurkat cells after IR could be of importance for the clinical treatment of leukemia patients. Here treatment is often a combination of chemotherapy and radiotherapy. On the background of the present data it is possible that radiation treatment could have previously unknown negative side effects. A rise in cell size, an increased adhesion to endothelial tissue as well as changes in the ion channel composition could lead to massive adhesion and transmigration of acute lymphoblastic leukemia (ALL) cells after radiotherapy. Drugs, which suppress specific integrin-β-1 mediated adhesion might reduce such negative side effects
Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells
Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naĂŻve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca2+, an upregulation of CD25 surface expression, interleukin-2 and interferon-Îł synthesis, elevated expression of Ca2+ sensitive K+ channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca2+-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients
The small neurotoxin apamin blocks not only small conductance Ca(2+) activated K(+) channels (SK type) but also the voltage dependent Kv1.3 channel.
Apamin is frequently used as a specific blocker of small-conductance Ca(2+)-activated (SK type) K(+) channels. Here we show that the small neurotoxin is not as specific as anticipated. It is also a high-affinity inhibitor with an IC50 of 13Â nM of the Kv1.3 channel; it blocks the latter with potency similar to the Kv1.3 blocker PAP-1. Since SK type channels and Kv1.3 channels are frequently coexpressed in different tissues such as cells of the immune system, apamin must be used with caution as a pharmacological tool
Ionizing radiation induces morphological changes and immunological modulation of Jurkat cells and naive T cells
Round-Robin Test to Prepare a Sample of a Multifunctional Layer Sprayed onto a CFC Substrate
Round-Robin Test to Prepare a Sample of a Multifunctional Layer Sprayed onto a CFC Substrate
image_1_Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells.tiff
<p>Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naïve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca<sup>2+</sup>, an upregulation of CD25 surface expression, interleukin-2 and interferon-γ synthesis, elevated expression of Ca<sup>2+</sup> sensitive K<sup>+</sup> channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca<sup>2+</sup> buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca<sup>2+</sup>-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients.</p