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A comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin

Thesis/Dissertation ·
OSTI ID:7165293
The mechanism by which tumor necrosis factor-alpha (TNF) initiates tumor cell destruction is unknown. We have approached this problem by comparing the biological properties of TNF with diphtheria toxin (DTx), a well-characterized cytotoxin. Initial studies with human U937 cells revealed that a transient exposure to low pH enhances the cytotoxic activity of TNF. Detailed studies on the interaction of TNF with pure lipid vesicles revealed that the acid-enhanced cytolytic activity of this cytokine is correlated with the acquisition of membrane binding and insertion properties. Significantly, an increase in target membrane stabilization was observed in the presence of TNF; hence, TNF is not directly lytic for membranes. In susceptible target cells, DTx induces the release of {sup 51}Cr- and {sup 75}Se-labeled proteins within 7 h. Although DTx-triggered cell death has generally been accepted as a straightforward effect of translation inhibition, little or no cell lysis was observed over a 20-30 h period when target cells were exposed to cycloheximide, amino acid deficient medium or metabolic poisons even though protein synthesis was inhibited to levels observed with DTx. The protein synthesis inhibition and cytolytic activities of DTx showed similar dose-dependencies, target cell specificities, and sensitivities to NH{sub 4}Cl inhibition. DTx-induced DNA fragmentation preceded cells lysis and did not occur in cells that were treated with the other protein synthesis inhibitors.
Research Organization:
California Univ., Los Angeles, CA (USA)
OSTI ID:
7165293
Country of Publication:
United States
Language:
English

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Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANIMALS
ANTIGENS
BETA DECAY RADIOISOTOPES
BIOLOGICAL FUNCTIONS
BIOLOGICAL PATHWAYS
CELL CONSTITUENTS
CELL MEMBRANES
CHROMIUM 51
CHROMIUM ISOTOPES
COMPARATIVE EVALUATIONS
DAYS LIVING RADIOISOTOPES
ELECTRON CAPTURE RADIOISOTOPES
ENZYME INHIBITORS
EVEN-ODD NUCLEI
FUNCTIONS
GROWTH FACTORS
INHIBITION
INTERMEDIATE MASS NUCLEI
ISOTOPE APPLICATIONS
ISOTOPES
LYSIS
MAMMALS
MAN
MATERIALS
MEMBRANES
MITOGENS
NUCLEI
ORGANIC COMPOUNDS
PRIMATES
PROTEINS
RADIOISOTOPES
SELENIUM 75
SELENIUM ISOTOPES
TOXIC MATERIALS
TOXINS
TRACER TECHNIQUES
TUMOR CELLS
VERTEBRATES