INTERLEUKIN-12, INTERFERON-GAMMA, AND TUMOR-NECROSIS-FACTOR-ALPHA ARETHE KEY CYTOKINES OF THE GENERALIZED SHWARTZMAN REACTION

The Shwartzman reaction is elicited by two injections of lipopolysacch aride (LPS) in mice. The priming LPS injection is given in the footpad , whereas the lethal LPS challenge is given intravenously 24 h later. The injection of interferon gamma (IFN-gamma) or interleukin 12 (IL-12 ) instead of the LPS priming injection induced the lethal reaction in mice further challenged with LPS. Antibodies against IFN-gamma when gi ven together with the priming agent, prevented the lethal reaction in mice primed with either LPS, IL-12, or IFN-gamma. Antibodies against I L-12, when given together with the priming agent, prevented the lethal reaction in mice primed with either LPS or IL-12 but not with IFN-gam ma. These results strongly suggest that LPS induces the release of IL- 12, that IL-12 induces the production of IFN-gamma, and that IFN-gamma is the cytokine that primes macrophages and other cell types. Upon LP S challenge, the lethal Shwartzman reaction is induced by a massive pr oduction of inflammatory cytokines that act on the target sites alread y sensitized by IFN-gamma. If mixtures of TNF and IL-1 or mixtures of TNF and IFN-gamma are used to challenge mice previously primed with IF N-gamma or IL-12, mortality is induced. In the same conditions, the in dividual cytokines or a mixture of IL-1 and IFN-gamma do not replace t he LPS challenge. When the mice are primed with LPS, the combination o f TNF, IL-1, and IFN-gamma induced only a partial mortality incidence suggesting that the involvement of other LPS-induced factors.