Cyclooxygenase inhibitors prevent the induction of tolerance to the toxic effects of tumor necrosis factor.

Nonsteroidal anti-inflammatory drugs, such as indomethacin (INDO), prevent acute toxicity caused by a single bolus injection of tumor necrosis factor (TNF). However, when given as a pretreatment to repetitive daily injections of TNF, INDO enhances toxicity. We investigated the effect of INDO on the induction of tolerance that develops after repeated injections of TNF, when administered in strictly dose- and schedule-dependent manners. Both INDO and another cyclooxygenase inhibitor, piroxicam, abrogated induction of a protective effect to a subsequent, potentially lethal challenge with TNF. At the same time, INDO blocked glucocorticoid induction by TNF. We conclude that cyclooxygenase inhibitors interfere with the pathway leading to protective tolerance. Hence, caution should be exercised when INDO is included in protocols involving multiple TNF administrations.