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 observ ed in mice rendered granulocytopenic (<0.05 x 10(9) granulocytes/litre ) with cyclophosphamide than in normal mice, Levels of circulating sol uble 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 observ ed, To investigate further the role of both sTNFR in inactivation of T NF, murine recombinant (r) TNF or human rTNF was injected in to normal and granulocytopenic mice, Higher TNF bioactivity was recovered in gr anulocytopenic mice than in normal mice after administration of murine rTNF, whereas, no difference in recovered TNF bioactivity was observe d after human rTNF, As murine TNFR-p75 does not bind to human TNF, thi s observation indicates that less sTNFR-p75 available for neutralizati on of TNF in the circulation in granulocytopenia results in enhanced T NF 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.