Granulocytopenia reduces release of soluble TNF receptor p75 in endotoxin-stimulated mice: a possible mechanism of enhanced TNF activity.
This study demonstrates that granulocytopenia alters the TNF response to endotoxin. Significantly higher levels of bioactive TNF were observed in mice rendered granulocytopenic (< 0.05 x 10(9) granulocytes/litre) with cyclophosphamide than in normal mice. Levels of circulating soluble TNF receptor p75 (sTNFR-p75) in response to endotoxin were higher in normal mice than in granulocytopenic mice whereas no difference in levels of circulating soluble TNF receptor p55 (sTNFR-p55) was observed. To investigate further the role of both sTNFR in inactivation of TNF, murine recombinant (r) TNF or human rTNF was injected in to normal and granulocytopenic mice. Higher TNF bioactivity was recovered in granulocytopenic mice than in normal mice after administration of murine rTNF, whereas, no difference in recovered TNF bioactivity was observed after human rTNF. As murine TNFR-p75 does not bind to human TNF, this observation indicates that less sTNFR-p75 available for neutralization of TNF in the circulation in granulocytopenia results in enhanced TNF bioactivity. Furthermore, endotoxin-induced lethality was increased in granulocytopenic mice. In summary, this study shows that endotoxin-induced release of sTNFR-p75 is reduced and TNF bioactivity increased in granulocytopenia. Our data suggest that release of sTNFR-p75 from granulocytes is a mechanism in the regulation of TNF bioactivity.
Steinshamn
S
S
Institute of Cancer Research, University Medical Center, Trondheim, Norway.
Bemelmans
M H
MH
Buurman
W A
WA
Waage
A
A
D000380:Agranulocytosis / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D003520:Cyclophosphamide / Q000633:toxicity; D004731:Endotoxins / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000503:physiopathology; D012995:Solubility; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D004731:Endotoxins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D003520:Cyclophosphamide