Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: Relation to plasma levels of interleukin-10 and interferon-γ

Abstract

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon γ (IFN-γ), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL- 12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 ± 515 pg/mLv 4,972 ± 732 pg/mL, P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL- 12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-γ were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-γ at 6 hours than those receiving a sublethal dose (P