Analysis of the effects of tumor necrosis factor inhibitors on human hematopoiesis.
Truncated soluble fragments of tumor necrosis factor (TNF) receptors have recently been isolated from human serum and urine. These shed forms of TNF receptors bind TNF-alpha and lymphotoxin and inhibit various effects of TNF in culture. In this study, we evaluated the role of these molecules in the hematopoietic system. TNF-alpha and lymphotoxin inhibited colony forming units granulocyte-macrophage (CFU-GM) and burst forming units-erythroid (BFU-E) in a dose-dependent fashion at concentrations ranging from 1 to 5,000 U/ml and 25 to 250 U/ml, respectively. TNF-alpha exerted a similar dose-dependent inhibitory effect on a CD34 enriched marrow cell population, suggesting that its effect is not mediated through CD34 accessory cells. Its suppressive effect was partially reversed by anti-TNF-alpha neutralizing antibodies, thus proving its specificity. Two shed forms of TNF receptors, TNF binding protein (TNF-bp) and TNF receptor fusion protein (TNFR-fc), had no significant effect on CFU-GM proliferation. Both molecules, however, significantly reversed the inhibitory effect of TNF-alpha (p < 0.015 and p < 0.03, respectively), whereas they had no effect on the lymphotoxin-induced CFU-GM growth inhibition. These results indicate that TNF-bp and TNFR-fc may modulate the inhibitory effects of TNF-alpha in the hematopoietic system.
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
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A
Ferrajoli
M
M
Talpaz
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R
Kurzrock
Z
Z
Estrov
D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D002352:Carrier Proteins; D008233:Lymphotoxin-alpha; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1