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Analysis of the effects of tumor necrosis factor inhibitors on human hematopoiesis
A Ferrajoli1, M Talpaz, R Kurzrock
1Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Abstract:
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.
Insights
Soluble tumor necrosis factor (TNF) receptor fragments inhibit hematopoietic cell growth. These TNF receptor fragments can reverse TNF-alpha
Area of Science:
- Hematology
- Immunology
- Molecular Biology
Background:
- Soluble fragments of tumor necrosis factor (TNF) receptors are found in human serum and urine.
- These shed receptors bind TNF-alpha and lymphotoxin, inhibiting TNF effects in vitro.
- The role of these molecules in the hematopoietic system requires investigation.
Purpose of the Study:
- To evaluate the role of soluble TNF receptor fragments in the hematopoietic system.
- To determine if TNF-alpha and lymphotoxin affect hematopoietic progenitor cells.
- To assess the ability of TNF receptor fragments to modulate these effects.
Main Methods:
- Assessing the dose-dependent effects of TNF-alpha and lymphotoxin on CFU-GM and BFU-E.
- Evaluating the impact of TNF-alpha on CD34+ enriched marrow cells.
- Testing the inhibitory and modulatory effects of TNF binding protein (TNF-bp) and TNF receptor fusion protein (TNFR-fc) on hematopoietic progenitor cells.
Main Results:
- TNF-alpha and lymphotoxin inhibited CFU-GM and BFU-E in a dose-dependent manner.
- TNF-alpha's suppressive effect on CD34+ cells was confirmed and partially reversed by neutralizing antibodies.
- TNF-bp and TNFR-fc did not affect CFU-GM proliferation but significantly reversed TNF-alpha's inhibitory effects, not lymphotoxin's.
Conclusions:
- TNF-alpha and lymphotoxin negatively impact hematopoietic progenitor cells.
- Shed TNF receptors (TNF-bp and TNFR-fc) specifically modulate TNF-alpha's inhibitory actions in hematopoiesis.
- These findings suggest a regulatory role for soluble TNF receptors in the hematopoietic system.