MACROPHAGE ENDOTOXIN TOLERANCE - EFFECT OF TNF OR ENDOTOXIN PRETREATMENT

Macrophages pretreated with low-dose endotoxin [lipopolysaccharide (LPS(1))] have an altered response to subsequent endotoxin (LPS(2)) stimulation, a process known as endotoxin tolerance. In this study we investigated whether the LPS(1) pretreatment effects were mediated primarily via tumor necrosis factor (TNF alpha). Murine peritoneal macrophages were pretreated in vitro with either TNF alpha or LPS(1) and the effects on mediator production in response to a second endotoxin exposure, LPS(2), were compared. Mediators in macrophage supernatant were measured using specific bioassays [TNF, interleukin-1 (IL-1), and IL-6] or enzymatic immunoassays [prostaglandin E(2) (PGE(2)) and TNF]. Macrophage production of all mediators was stimulated by endotoxin in the absence of LPS(1) pretreatment. Pretreatment with LPS, completely inhibited 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 initial exposure to endotoxin, LPS(1), is not solely responsible for the observed alterations in macrophage mediator release following a subsequent endotoxin stimulus (LPS(2)). Thus, the data suggest that endotoxin tolerance is mediated primarily by factors other than TNF. (C) 1994 Academic Press, Inc.