Dissociation of IFN-γ from IL-12 and IL-18 production during endotoxin tolerance

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Abstract
Endotoxin tolerance was induced in mice following one, two or three injections of low amounts of lipopolysaccharide (LPS) before a further LPS injection, and circulating cytokines were analyzed 1.5 h and 3 h after LPS challenge. Three different patterns of cytokine production were obtained. In a first group of cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6) and gamma interferon (IFN-γ), the reduction of plasma peak levels was already significantly pronounced after one tolerizing injection of LPS. The second group of cytokines includes the CC chemokine KC, the CXC chemokine monocyte-chemo-attractant protein-1 (MCP-1) and IL-12. The plasma levels of these cytokines were modestly reduced, and the reduction was more pronounced with increasing numbers of tolerizing injections of LPS. The third group of cytokines includes IL-1β and IL-18, the levels of which 3 h after LPS challenge (i.e. at the peak timing) remained essentially similar to those of control mice and after 1.5 h were even enhanced. Altogether, these data illustrate that, in tolerized animals, in vivo regulation of cytokine production differs greatly among different mediators and that immunoparalysis is not a general state. Furthermore, despite the presence of large amounts of IL-12 and IL-18, IFN-γ was essentially suppressed in tolerized animals.