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

Download Full-text

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.

Journal of Experimental Medicine ◽

10.1084/jem.167.3.1067 ◽

1988 ◽

Vol 167 (3) ◽

pp. 1067-1085 ◽

Cited By ~ 173

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.

Download Full-text

Release of tumor necrosis factor by human polymorphonuclear leukocytes

Blood ◽

10.1182/blood.v76.7.1405.1405 ◽

1990 ◽

Vol 76 (7) ◽

pp. 1405-1409 ◽

Cited By ~ 85

Author(s):

JY Djeu ◽

D Serbousek ◽

DK Blanchard

Keyword(s):

Tumor Necrosis Factor ◽

Polymorphonuclear Leukocytes ◽

Tumor Necrosis ◽

Polymorphonuclear Neutrophils ◽

Opportunistic Fungi ◽

Produce Tumor Necrosis Factor ◽

Human Polymorphonuclear Leukocytes ◽

Block Protein Synthesis ◽

Granular Lymphocytes ◽

Necrosis Factor

Abstract Evidence is presented that human polymorphonuclear neutrophils (PMN) can be induced to produce tumor necrosis factor (TNF). Other investigators have previously reported that TNF has been induced from macrophages by bacteria and, more recently, from natural killer cells by certain tumor cells. Our laboratory has reported that the opportunistic fungi, Candida albicans, can induce TNF, not only from human monocytes, but also from Percoll-fractionated large granular lymphocytes. We now report that incubation of PMN with C albicans for 3 hours was sufficient for detection of TNF release, and peak induction was observed at 8 to 18 hours. This release was inhibitable by actinomycin D, an inhibitor of RNA synthesis, as well as by emetine and cycloheximide, which block protein synthesis. The TNF produced by PMN was neutralized by specific monoclonal antibodies against human TNF. These results represent an important finding that TNF production is a normal response of PMN to stimulation by fungi such as C albicans and suggest that the release of TNF may be related to autocrine activation of PMN effector function to control Candida growth.

Download Full-text

Rapid acquisition of an enhanced capacity to produce tumor necrosis factor, alpha/beta interferon, and interleukin 6 after implantation of tumor cells

Cytokine ◽

10.1016/1043-4666(91)90043-d ◽

1991 ◽

Vol 3 (5) ◽

pp. 398-406 ◽

Cited By ~ 6

Author(s):

Alexander L. Rakhmilevich ◽

Robert J. North

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Cells ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Rapid Acquisition ◽

Produce Tumor Necrosis Factor ◽

Factor Alpha ◽

Alpha Beta ◽

Necrosis Factor

Download Full-text

Anti-tumor effect of tumor necrosis factor combined with electrotherapy on mouse sarcoma

Anti-Cancer Drugs ◽

10.1097/00001813-199402000-00011 ◽

1994 ◽

Vol 5 (1) ◽

pp. 69-74 ◽

Cited By ~ 7

Author(s):

Gregor Sersa ◽

Rastko Golouh ◽

Damijan Miklavčič

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Mouse Sarcoma ◽

Necrosis Factor

Download Full-text

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

Tumor Necrosis Factor: Structure, Mechanism of Action, Role in Disease and Therapy ◽

10.1159/000417363 ◽

2015 ◽

pp. 194-202

Author(s):

Jay L. Rothstein ◽

Hans Schreiber

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Hemorrhagic Necrosis ◽

Necrosis Factor

Download Full-text

Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice

Blood ◽

10.1182/blood.v74.1.130.130 ◽

1989 ◽

Vol 74 (1) ◽

pp. 130-138 ◽

Cited By ~ 113

Author(s):

RA Johnson ◽

TA Waddelow ◽

J Caro ◽

A Oliff ◽

GD Roodman

Keyword(s):

Tumor Necrosis Factor ◽

Nude Mice ◽

Tumor Necrosis ◽

Chinese Hamster ◽

Anemia Of Chronic Disease ◽

Produce Tumor Necrosis Factor ◽

Tnf Gene ◽

Necrosis Factor

Abstract The anemia of chronic disease (ACD) is associated with conditions in which macrophage activation occurs. Activated marrow macrophages suppress erythropoiesis in vitro and produce tumor necrosis factor (TNF). Therefore, we tested the effects of chronic in vivo exposure to TNF to determine if it was a candidate for a mediator of ACD. Nude mice were inoculated with Chinese hamster ovary (CHO) cells expressing the human TNF gene or with control cells containing the transfection vector alone. The TNF mice promptly became reticulocytopenic, and after 3 weeks their corrected reticulocytes were 2.6% +/- 0.7% as compared with 7.3% +/- 4% in control mice. The hematocrit at 3 weeks was 28.4% +/- 1.7% in TNF mice as compared with 46% +/- 0.8% in control mice. This anemia was also associated with low serum iron and normal iron stores and increased erythropoietin (Epo) levels. The TNF mice showed an absolute monocytosis with twice the number of circulating monocytes as control mice and had M-colony-stimulating factor (CSF) activity in their serum. The TNF mice also became mildly thrombocytopenic. Marrow CFU-E and BFU-E were profoundly decreased (1.2 +/- 0.2 x 10(3) v 8.6 +/- 0.2 x 10(4) CFU-E per femur, and 6.5 +/- 1 x 10(2) v 8.5 +/- 0.2 x 10(4) BFU-E per femur). Splenic CFU-E and BFU-E were similarly depressed. In contrast, marrow CFU-GM and CFU-GEMM were not affected. The residual BFU-E in TNF mice were relatively resistant to TNF as compared with control mice. These data demonstrate that TNF preferentially inhibits erythropoiesis in vivo and may be important in the pathogenesis of ACD.

Download Full-text