Induction of tolerance to lipopolysaccharide (LPS)-D-galactosamine lethality by pretreatment with LPS is mediated by macrophages

In mice treated with D-galactosamine, lipopolysaccharide (LPS) exhibits enhanced toxicity (C. Galanos, M. A. Freudenberg, and W. Reutter, Proc. Natl. Acad. Sci. USA 76:5939-5943, 1979). Pretreatment of mice with LPS before D-galactosamine rendered them tolerant to the enhanced lethal effect of LPS. Tolerance was established at 1 h after LPS injection and, depending on the dose of LPS used for pretreatment, lasted for up to 48 h. With C3H/HeJ mice with acquired sensitivity to LPS (M. A. Freudenberg, D. Keppler, and C. Galanos, Infect. Immun. 51:891-895, 1986), i.e., mice that had been administered C3H/HeN macrophages, pretreatment with LPS induced tolerance only if the C3H/HeN macrophages were already present at the time of pretreatment. This indicates that, like lethality, induction of tolerance by LPS is a macrophage-mediated phenomenon. Direct interaction of LPS with macrophages is the first step in the initiation of tolerance or toxicity. C3H/HeN macrophages (2 X 10(7], incubated with minute amounts of LPS (0.5 to 0.02 microgram) in vitro and transferred subsequently to C3H/HeJ mice, induced lethality when administered together with or after D-galactosamine and tolerance when injected before D-galactosamine. Macrophages activated in vitro lost their tolerance- and lethality-inducing properties upon further incubation in LPS-free culture medium for 18 h. Such macrophages could be successfully restimulated by a new addition of LPS.