Dissociation of IFN-gamma from IL-12 and IL-18 production during endotoxintolerance

Endotoxin tolerance was induced in mice following one, two or three injecti ons of low amounts of lipopolysaccharide (LPS) before a further LPS injecti on, and circulating cytokines were analyzed 1.5 h and 3 h after LPS challen ge. Three different patterns of cytokine production were obtained. In a fir st group of cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6) and gamma interferon (IFN-gamma), the reduction of plasma peak leve ls was already significantly pronounced after one tolerizing injection of L PS. The second group of cytokines includes the CC chemokine KC, the CXC che mokine monocyte-chemo-attractant protein-1 (MCP-1) and IL-12. The plasma le vels of these cytokines were modestly reduced, and the reduction was more p ronounced with increasing numbers of tolerizing injections of LPS. The thir d group of cytokines includes IL-1 beta 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, th ese data illustrate that, in tolerized animals, in vivo regulation of cytok ine production differs greatly among different mediators and that immunopar alysis is not a general state. Furthermore, despite the presence of large a mounts of IL-12 and IL-18, IFN-gamma was essentially suppressed in tolerize d animals.