Tumor Necrosis Factor and Complement: Induction of Hemorrhagic Necrosis in Normal Tissue1

2015 ◽  
pp. 194-202
Author(s):  
Jay L. Rothstein ◽  
Hans Schreiber
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Hemorrhagic Necrosis ◽  
Necrosis Factor

scholarly journals Nonhematopoietic cells selected for resistance to tumor necrosis factor produce tumor necrosis factor.

1986 ◽  
Vol 164 (4) ◽  
pp. 1350-1355 ◽  
Author(s):  
B Y Rubin ◽  
S L Anderson ◽  
S A Sullivan ◽  
B D Williamson ◽  
E A Carswell ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cytotoxic Action ◽  
Surface Receptors ◽  
L Cells ◽  
Produce Tumor Necrosis Factor ◽  
Hemorrhagic Necrosis ◽  
Resistant Lines ◽  
Mouse Sarcoma ◽  
Necrosis Factor

TNF-resistant lines of L cells can be derived from TNF-sensitive populations by repeated exposure to TNF, and these resistant L cells, in contrast to sensitive L cells and other types of cells, lack demonstrable cell surface receptors for TNF. We have now found that TNF-resistant L cells produce a factor that is cytotoxic for L cells and has the following distinguishing characteristics of mouse TNF: it is a protein of 43 kD, composed of 16 kD subunits, that competes with TNF for receptor binding, induces hemorrhagic necrosis of the TNF-sensitive mouse sarcoma Meth A, has synergistic cytotoxic action with interferon, and its activity is neutralized by antibody to TNF. The two conclusions of this study are that cells selected for TNF resistance spontaneously produce a molecule resembling macrophage TNF, and that cells of nonhematopoietic origin are capable of producing TNF.

scholarly journals The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity.

1978 ◽  
Vol 148 (6) ◽  
pp. 1560-1569 ◽  
Author(s):  
M J Berendt ◽  
R J North ◽  
D P Kirstein
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Immunity ◽  
Tumor Necrosis ◽  
Temporal Relationship ◽  
Tumor Regression ◽  
Effector T Cells ◽  
Hemorrhagic Necrosis ◽  
Concomitant Immunity ◽  
Necrosis Factor

It was shown that of four syngeneic, murine tumors investigated, only those that evoked the generation of a state of concomitant anti-tumor immunity were susceptible to endotoxin-induced regression. Moreover, the temporal relationship between the generation of concomitant immunity and the onset of susceptibility to endotoxin-induced regression points to the likely possibility that tumor regression depends on the preceding acquisition of the specifically-sensitized, effector T cells that express concomitant immunity. It is suggested that endotoxin-induced hemorrhagic necrosis which invariably precedes tumor regression serves to create conditions inside the tumor that are conducive to the entry and the functioning of effector T cells. It is also suggested that tumor necrosis factor causes hemorrhagic necrosis rather than tumor regression.

scholarly journals Glucocorticoid-mediated inhibition of endotoxin-induced intratumor tumor necrosis factor production and tumor hemorrhagic necrosis and regression.

1989 ◽  
Vol 170 (3) ◽  
pp. 703-710 ◽  
Author(s):  
R J North ◽  
E A Havell
Keyword(s):  
Tumor Necrosis Factor ◽  
Intravenous Injection ◽  
Subcutaneous Injection ◽  
Tumor Necrosis ◽  
Complete Regression ◽  
Tumor Necrosis Factor Production ◽  
The Core ◽  
Hemorrhagic Necrosis ◽  
Extensive Necrosis ◽  
Necrosis Factor

Intravenous injection of 25 micrograms of bacterial endotoxin on day 9 of growth of the SA1 sarcoma results in extensive necrosis of the core of this tumor and in its subsequent complete regression. Tumor hemorrhagic necrosis and regression failed to occur in mice that were given a subcutaneous injection of cortisone acetate or dexamethasone 12 h before being giving endotoxin. Inhibition of tumor hemorrhagic necrosis and regression by glucocorticoids was associated with inhibition of endotoxin-induced intratumor TNF production that normally takes place several h after endotoxin is given. In contrast, glucocorticoids had no effect on the ability of intravenously injected rTNF to cause tumor hemorrhagic necrosis and regression. The results lend further support to the belief that TNF is the predominant mediator of endotoxin-induced hemorrhagic necrosis of established murine tumors, and that hemorrhagic necrosis is a prerequisite for the immunologically mediated regression that follows.

scholarly journals The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity.

1988 ◽  
Vol 167 (3) ◽  
pp. 1067-1085 ◽  
Author(s):  
E A Havell ◽  
W Fiers ◽  
R J North
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Regression ◽  
Cytotoxic Action ◽  
Complete Regression ◽  
Severe Toxicity ◽  
Hemorrhagic Necrosis ◽  
Necrosis Factor

The ability of murine recombinant tumor necrosis factor (rTNF) and natural TNF in tumor-necrotizing serum (TNS) to cause regression of the SA1 sarcoma was investigated. We found that to cause regression of a 9-d SA1 sarcoma, near lethal quantities of rTNF and TNS had to be given to the host. However, even at these highly toxic doses, rTNF was not reliable at causing complete tumor regression. On the other hand, both types of TNF were reliable at causing a tumor hemorrhagic reaction that resulted in the destruction of greater than 75% of the tumor's center in 24 h. The TNF-induced hemorrhagic reaction involved the development of numerous petechial hemorrhages in the tumor's vascular bed, which apparently resulted from destruction of the tumor's blood vessels. It was possible to follow the development of the hemorrhagic reaction against time after giving rTNF or TNS by measuring the intratumor extravasation of 51Cr-labeled syngeneic red cells. According to this method, TNF-induced intratumor hemorrhaging was in progress within 1 h of giving TNF and continued for about a 6-h period. However, the hemorrhagic reaction was greatly reduced and complete regression of the rim of the living tumor tissue that survived hemorrhagic necrosis failed to occur, if SA1 sarcoma was growing in T cell-deficient (TXB) mice. This indicates that the TNF-induced hemorrhagic reaction is partly dependent, and the tumor regression that follows is completely dependent on host immunocompetence. This suggests in turn, that rTNF does not directly destroy SA1 tumor cells in vivo, even though it was shown that it can destroy SA1 tumor cells in vitro. This interpretation is supported by the additional findings that rTNF was no more therapeutic against a 3-d (3-mm) SA1 than against a 9-d (8-mm) SA1, and was no more therapeutic when injected directly into the tumor than when injected intravenously. Lastly it was possible to completely inhibit the ability of rTNF and TNS to cause tumor hemorrhagic necrosis and regression by infusing the host with a monospecific, polyvalent anti-rTNF antibody that neutralized the cytotoxic action of rTNF in vitro.

Tumor Necrosis Factor in the Pathogenesis of Human Diseases

1992 ◽  
Vol 5 (2) ◽  
pp. 131-134
Author(s):  
P. Ghezzi
Keyword(s):  
New York ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Biological Activities ◽  
Laboratory Animals ◽  
Hemorrhagic Necrosis ◽  
Necrosis Factor

This paper will deal with the role of tumor necrosis factor (TNF) in the pathogenesis of various diseases. However, it will be important to remember that originally TNF was characterized as an antitumor factor. In fact, it was known that endotoxin was able to induce hemorrhagic necrosis of some tumors in mice. In 1975 Carswell et al. demonstrated the presence of a tumor necrotizing activity (termed “tumor necrosis serum”) in the sera of mice primed with C. parvum or BCG, and subsequently injected with endotoxin (1). Later it was found that this factor was a macrophage product and was termed TNF. In vivo TNF induced hemorrhagic necrosis of Meth A sarcoma and in vitro demonstrated cytotoxic activity against various tumor cell lines (2). In 1984, TNF was purified and its cDNA was cloned, and the production of substantial amounts of recombinant TNF allowed the characterization of its various biological activities (3). In parallel to these studies on tumor necrosis, the group of Cerami, at the Rockefeller University in New York was studying the mechanisms of cachexia and wasting associated with infection. They found that infection or injection of endotoxin in laboratory animals resulted in a marked hypertrygliceridemia, which was associated with an inhibition of lipoprotein lipase. They hypothesized that a host-derived mediator was responsible for this and other metabolic derangements observed in infection. This factor, which was termed “cachectin”, was later found to be produced by macrophages, and once it was purified and sequenced it became clear that TNF and cachectin were identical (4).

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