Prevention of the toxic action of tumor necrosis factor by cyclooxygenase inhibitor and leukopenia.

The interactions between leukopenia induced by vinblastine and the cyclooxygenase inhibitor indomethacin on the toxicity of tumor necrosis factor (TNF) were studied. When indomethacin was injected 60 min before the administration of recombinant TNF, it provided significant protection against rapid killing by TNF; leukopenia also prevented the toxic action of TNF. However, their inhibition of the activity of TNF was not sufficient, and 17-25% of the rats died within 48 hr following TNF administration. Every rat that received peritoneal polymorphonuclear leukocytes (PMNLs) died within 24 hr following the administration of TNF. On the other hand, administration of indomethacin to the rats in leukopenia prevented the toxic action of TNF completely, and all rats lived for 48 hr and showed no changes, compared to normal rats, in hematocrit, plasma transaminase, and body temperature. From these findings, the toxic action of TNF seems to result from increases in synthesis of prostaglandins (PGs) and activation of PMNLs.