MACROPHAGE ENDOTOXIN TOLERANCE - EFFECT OF TNF OR ENDOTOXIN PRETREATMENT

Macrophages pretreated with low-dose endotoxin [lipopolysaccharide (LP S(1))] have an altered response to subsequent endotoxin (LPS(2)) stimu lation, a process known as endotoxin tolerance. In this study we inves tigated whether the LPS(1) pretreatment effects were mediated primaril y via tumor necrosis factor (TNF alpha). Murine peritoneal macrophages were pretreated in vitro with either TNF alpha or LPS(1) and the effe cts on mediator production in response to a second endotoxin exposure, LPS(2), were compared. Mediators in macrophage supernatant were measu red using specific bioassays [TNF, interleukin-1 (IL-1), and IL-6] or enzymatic immunoassays [prostaglandin E(2) (PGE(2)) and TNF]. Macropha ge production of all mediators was stimulated by endotoxin in the abse nce of LPS(1) pretreatment. Pretreatment with LPS, completely inhibite d LPS(2)-triggered TNF release whereas preexposure to TNF alpha had no effect. In contrast, LPS(1) pretreatment significantly augmented IL-1 and PGE(2) release in response to LPS(2), whereas pretreatment using either high- or low dose TNF alpha did not. TNF, stimulated by an init ial exposure to endotoxin, LPS(1), is not solely responsible for the o bserved alterations in macrophage mediator release following a subsequ ent endotoxin stimulus (LPS(2)). Thus, the data suggest that endotoxin tolerance is mediated primarily by factors other than TNF. (C) 1994 A cademic Press, Inc.