Prothrombotic effects of tumor necrosis factor alpha in vivo are amplified by the absence of TNF-alpha receptor subtype 1 and require TNF-alpha receptor subtype 2

Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha (TNF-alpha) when these cells are triggered with lipopolysaccharide and other agonists in culture. 40% inhibition occurs at the clinically achievable dose of the drug of 1 micrograms/ml. In contrast, the amount of total protein and individual proteins labeled with [35S]methionine and expressed on SDS-PAGE are not influenced. The amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony-stimulating factor produced by monocytes remain unaltered. The selectivity of this drug may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.

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Abnormal lymphokine production: a novel feature of the genetic disease Fanconi anemia. II. In vitro and in vivo spontaneous overproduction of tumor necrosis factor alpha

Blood ◽

10.1182/blood.v83.5.1216.1216 ◽

1994 ◽

Vol 83 (5) ◽

pp. 1216-1225 ◽

Cited By ~ 89

Author(s):

F Rosselli ◽

J Sanceau ◽

E Gluckman ◽

J Wietzerbin ◽

E Moustacchi

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Fanconi Anemia ◽

Tumor Necrosis ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Abstract We have previously shown an unbalanced cytokine production in Fanconi anemia (FA) cells, ie, an underproduction of interleukin 6 (IL-6) during growth. Among a number of cytokines analyzed, the only other anomalies detected concern tumor necrosis factor alpha (TNF alpha). In comparison to normal cells, this cytokine is overproduced by FA lymphoblasts from the four genetic complementation groups. Indeed, up to an eight-fold increase in TNF alpha is observed in the growth medium of FA cells. Moreover, addition of anti-TNF alpha antibodies partially corrects the FA hypersensitivity to treatment by mitomycin C (MMC). Treatment of FA cells with IL-6, which partially restored an almost normal sensitivity to MMC of FA cells also reduces the TNF alpha overproduction in FA lymphoblasts. No anomalies at the molecular level (Southern and Northern blot analyses) are detected for the TNF alpha gene and its mRNA. We have investigated the in vivo situation by assaying TNF alpha levels in the serum from FA homozygotes and obligate heterozygotes. In contrast to normal healthy donors or to aplastic anemia patients in whom serum TNF alpha is present only in trace amounts, all 36 FA patients and 21 FA parents monitored show a significantly (P < .001) higher level of serum TNF alpha activity. Consequently, abnormal TNF alpha production seems to be associated with the FA genetic background.

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In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and erythroleukemic mice: characterization and therapeutic applications

Blood ◽

10.1182/blood.v72.6.1875.1875 ◽

1988 ◽

Vol 72 (6) ◽

pp. 1875-1883 ◽

Cited By ~ 25

Author(s):

CS Johnson ◽

MJ Chang ◽

P Furmanski

Keyword(s):

Bone Marrow ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Late Stage ◽

Tumor Necrosis ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Abstract The effects of recombinant, macrophage-derived, murine tumor necrosis factor-alpha (TNF-alpha) on hematopoiesis in vivo has been examined in normal mice and in Friend virus (FV)-induced erythroleukemic mice. Intravenous (IV) administration of a single dose of recombinant murine TNF-alpha (10(5) U per mouse) significantly suppressed normal and leukemic late-stage erythropoiesis as measured by numbers of mature erythroid colony forming cells (CFU-E) in the bone marrow and spleen and by peripheral blood reticulocyte counts. In normal animals, the immature erythroid (BFU-E), macrophage (CFU-M), and granulocyte- macrophage (CFU-GM) compartments were significantly stimulated by TNF- alpha in both the bone marrow and the spleen. In the bone marrow of leukemic mice, the BFU-E, CFU-GM, and CFU-M progenitor cell compartments were also stimulated by treatment with the monokine. In the spleens of leukemic mice (the primary site of FV leukemia cell accumulation), relative numbers of BFU-E and CFU-GM were increased by TNF-alpha, while those of CFU-M were suppressed. TNF-alpha caused a rapid decrease in the markedly elevated spleen weights of progressively leukemic mice, and in multiple doses it caused complete clinical disease regression in a significant percentage of leukemic animals. The combination of TNF-alpha with interferon-gamma (IFN-gamma) increased the incidence of leukemia regression, compared with TNF-alpha alone. These results show that TNF-alpha exerts a suppressive influence on late-stage erythropoiesis in vivo and suggest that this effect might be exploited in the treatment of acute erythroleukemia, erythroid hyperplasias, and related diseases.

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Somnogenic, pyrogenic, and anorectic activities of tumor necrosis factor-alpha and TNF-alpha fragments

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.263.3.r708 ◽

1992 ◽

Vol 263 (3) ◽

pp. R708-R715 ◽

Cited By ~ 14

Author(s):

L. Kapas ◽

L. Hong ◽

A. B. Cady ◽

M. R. Opp ◽

A. E. Postlethwaite ◽

...

Keyword(s):

Amino Acid ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Exogenously administered tumor necrosis factor-alpha (TNF-alpha) elicits several symptoms of generalized infections such as fever, increased sleep, and anorexia. The aim of the present work was to localize these effects of TNF-alpha to specific amino acid sequences of the parent molecule by characterizing the in vivo and in vitro activities of several synthetic TNF-alpha fragments. Intracerebroventricular injection of TNF-alpha elicited dose-dependent fevers and increases in non-rapid-eye-movement sleep (NREMS) in rabbits. Four fragments also promoted NREMS and five elicited monophasic fevers. All of the somnogenic fragments share the amino acid sequence 31-36. In rats, TNF-alpha and one of the fragments [TNF-alpha-(69-100)] suppressed 12-h food intake. Furthermore, TNF-alpha increased the expression of the intercellular adhesion molecule-1 and enhanced interferon-gamma-induced HLA-DR expression in human glioblastoma cell line. In contrast, none of the fragments possessed these in vitro activities. Our in vivo results support the concept that there are biologically active regions in the TNF-alpha molecule.

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Tumor necrosis factor-alpha induces c-jun during the regenerative response to liver injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.267.4.g552 ◽

1994 ◽

Vol 267 (4) ◽

pp. G552-G561 ◽

Cited By ~ 14

Author(s):

A. M. Diehl ◽

M. Yin ◽

J. Fleckenstein ◽

S. Q. Yang ◽

H. Z. Lin ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Liver Injury ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Binding Activity ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

After liver injury, remaining hepatocytes proliferate to regenerate the liver. Although the precise mechanisms that initiate and localize regeneration are unknown, local induction of c-jun is a critical, early step in the response. Treatment of rats with antibodies to tumor necrosis factor-alpha (TNF-alpha), a mediator of liver injury, inhibits regenerative induction of jun nuclear kinase activity and nuclear c-jun expression and alters the DNA binding activity of the c-jun transcription factor, AP-1, in liver. Pretreatment with anti-TNF antibodies does not affect pulmonary or renal c-jun expression or AP-1 binding activity post-partial hepatectomy. In primary hepatocyte cultures, TNF-alpha directly promotes the proliferative actions of mitogens, supporting in vivo evidence that it sensitizes hepatocytes to mitogens. Thus local release of TNF may act in a paracrine fashion to initiate regeneration in the injured liver by promoting induction of critical growth-related genes, such as c-jun.

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Effects of RP 55778, a tumor necrosis factor alpha synthesis inhibitor, on antiviral activity of dideoxynucleosides.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.4.875 ◽

1997 ◽

Vol 41 (4) ◽

pp. 875-877 ◽

Cited By ~ 4

Author(s):

P Clayette ◽

N Dereuddre-Bosquet ◽

M Martin ◽

P Fretier ◽

D Dormont

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Tnf Alpha ◽

Resting Cells ◽

Synthesis Inhibitor ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

Tumor necrosis factor alpha (TNF-alpha) is overexpressed during human immunodeficiency virus (HIV) infection. RP 55778, a TNF-alpha synthesis inhibitor, decreases HIV replication in monocytes/macrophages. Therapeutic use of RP 55778 in vivo, like that of other biological response modifiers, would theoretically require association with dideoxynucleosides. We have evaluated here the combinatory effects of zidovudine (AZT) or dideoxyinosine (ddI) and RP 55778. This TNF-alpha inhibitor antagonizes the antiviral effects of both dideoxynucleosides, especially AZT. The more favorable anti-HIV activity of ddI in resting cells may explain these unequal degrees of antagonism.

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Abnormal lymphokine production: a novel feature of the genetic disease Fanconi anemia. II. In vitro and in vivo spontaneous overproduction of tumor necrosis factor alpha

Blood ◽

10.1182/blood.v83.5.1216.bloodjournal8351216 ◽

1994 ◽

Vol 83 (5) ◽

pp. 1216-1225 ◽

Cited By ~ 1

Author(s):

F Rosselli ◽

J Sanceau ◽

E Gluckman ◽

J Wietzerbin ◽

E Moustacchi

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Fanconi Anemia ◽

Tumor Necrosis ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

We have previously shown an unbalanced cytokine production in Fanconi anemia (FA) cells, ie, an underproduction of interleukin 6 (IL-6) during growth. Among a number of cytokines analyzed, the only other anomalies detected concern tumor necrosis factor alpha (TNF alpha). In comparison to normal cells, this cytokine is overproduced by FA lymphoblasts from the four genetic complementation groups. Indeed, up to an eight-fold increase in TNF alpha is observed in the growth medium of FA cells. Moreover, addition of anti-TNF alpha antibodies partially corrects the FA hypersensitivity to treatment by mitomycin C (MMC). Treatment of FA cells with IL-6, which partially restored an almost normal sensitivity to MMC of FA cells also reduces the TNF alpha overproduction in FA lymphoblasts. No anomalies at the molecular level (Southern and Northern blot analyses) are detected for the TNF alpha gene and its mRNA. We have investigated the in vivo situation by assaying TNF alpha levels in the serum from FA homozygotes and obligate heterozygotes. In contrast to normal healthy donors or to aplastic anemia patients in whom serum TNF alpha is present only in trace amounts, all 36 FA patients and 21 FA parents monitored show a significantly (P < .001) higher level of serum TNF alpha activity. Consequently, abnormal TNF alpha production seems to be associated with the FA genetic background.

Download Full-text

In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and erythroleukemic mice: characterization and therapeutic applications

Blood ◽

10.1182/blood.v72.6.1875.bloodjournal7261875 ◽

1988 ◽

Vol 72 (6) ◽

pp. 1875-1883

Author(s):

CS Johnson ◽

MJ Chang ◽

P Furmanski

Keyword(s):

Bone Marrow ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Late Stage ◽

Tumor Necrosis ◽

Tnf Alpha ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

The effects of recombinant, macrophage-derived, murine tumor necrosis factor-alpha (TNF-alpha) on hematopoiesis in vivo has been examined in normal mice and in Friend virus (FV)-induced erythroleukemic mice. Intravenous (IV) administration of a single dose of recombinant murine TNF-alpha (10(5) U per mouse) significantly suppressed normal and leukemic late-stage erythropoiesis as measured by numbers of mature erythroid colony forming cells (CFU-E) in the bone marrow and spleen and by peripheral blood reticulocyte counts. In normal animals, the immature erythroid (BFU-E), macrophage (CFU-M), and granulocyte- macrophage (CFU-GM) compartments were significantly stimulated by TNF- alpha in both the bone marrow and the spleen. In the bone marrow of leukemic mice, the BFU-E, CFU-GM, and CFU-M progenitor cell compartments were also stimulated by treatment with the monokine. In the spleens of leukemic mice (the primary site of FV leukemia cell accumulation), relative numbers of BFU-E and CFU-GM were increased by TNF-alpha, while those of CFU-M were suppressed. TNF-alpha caused a rapid decrease in the markedly elevated spleen weights of progressively leukemic mice, and in multiple doses it caused complete clinical disease regression in a significant percentage of leukemic animals. The combination of TNF-alpha with interferon-gamma (IFN-gamma) increased the incidence of leukemia regression, compared with TNF-alpha alone. These results show that TNF-alpha exerts a suppressive influence on late-stage erythropoiesis in vivo and suggest that this effect might be exploited in the treatment of acute erythroleukemia, erythroid hyperplasias, and related diseases.

Download Full-text