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Kupffer cells (KC) of the hepatic sinusoid respond to endotoxemia by producing mediators which promote or inhibit systemic inflammatory responses. Sublethal lipopolysaccharide (LPS) pretreatment confers tolerance to the lethality of a subsequent LPS exposure. However, the precise role of the KC in endotoxin tolerance (ET) remains unclear. This study evaluated the effect of ET induction upon the rat KC production of the mediators tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and interleukin-6 (IL-6), and upon the in vivo phagocytic capacity of the KCs. 3 days prior to KC isolation, age-matched rats received either 5 mg/kg LPS (ET) or normal saline (nontolerant, NT), which protected 100% of the ET rats against an LPS dose 3 days later which was lethal in 72% of NT rats. On an in vitro LPS rechallenge, ET KC produced significantly lower amounts of TNF than NT KC (ρ < .01). In contrast, the ET KC produced significantly more PGE2 (ρ < .05) and IL-6 (ρ < .001) than the NT KC. The percentage of KC phagocytosing fluorescent latex spheres in vivo was increased 7-fold in the ET rats. Thus, ET induction, which protects rats against subsequent lethal endotoxemia, selectively alters KC mediator production and phagocytic capacity. These findings strongly implicate the KC in the mediation of early endotoxin tolerance.